"Anticancer Res"[jour]; +57 new citations

Anticancer Res




. 2020 Sep;40(9):5049-5057. doi: 10.21873/anticanres.14508.
Anticancer Effect of a Spiro-acridine Compound Involves Immunomodulatory and Anti-angiogenic Actions
SÂmia Sousa Duarte 1, Daiana Karla Frade Silva 1, ThaÍs Mangeon Honorato Lisboa 1, Rawny Galdino Gouveia 1, Rafael Carlos Ferreira 1, Ricardo OlÍmpio DE Moura 2, Jamire Muriel DA Silva 3, Éssia DE Almeida Lima 4, Sandra Rodrigues-Mascarenhas 1 4, Patricia Mirella DA Silva 5, Davi Felipe Farias 6, Juliana Alves DA Costa Ribeiro Souza 6, Karina Carla DE Paula Medeiros 7, Juan Carlos Ramos GonÇalves 8, Marianna Vieira Sobral 9 8
Affiliations expand
PMID: 32878793
DOI: 10.21873/anticanres.14508

Abstract


Background/aim: Studies with acridine compounds have reported anticancer effects. Herein, we evaluated the toxicity and antitumor effect of the (E)-1'-((4-chlorobenzylidene)amino)-5'-oxo-1',5'-dihydro-10H-spiro[acridine-9,2'-pyrrole]-4'-carbonitrile (AMTAC-06), a promising anticancer spiro-acridine compound.

Materials and methods: The toxicity of AMTAC-06 was evaluated on zebrafish and mice. Antitumor activity was assessed in Ehrlich ascites carcinoma model. Effects on angiogenesis, cytokine levels and cell cycle were also investigated.

Results: AMTAC-06 did not induce toxicity on zebrafish and mice (LD50 approximately 5000 mg/kg, intraperitoneally). No genotoxicity was observed on micronucleus assay. AMTAC-06 significantly reduced the total viable Ehrlich tumor cells and increased sub-G1 peak, suggesting apoptosis was triggered. Moreover, the compound significantly decreased the density of peritumoral microvessels, indicating an anti-angiogenic action, possibly dependent on the cytokine modulation (TNF-α, IL-1β and IFN-γ). No significant toxicological effects were recorded for AMTAC-06 on tumor transplanted animals.

Conclusion: AMTAC-06 has low toxicity and a significant antitumor activity.

Keywords: Ehrlich ascites carcinoma model; Spiro-acridine; anti-angiogenic activity; antitumor activity; immunomodulation; zebrafish.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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2
Review
Anticancer Res




. 2020 Sep;40(9):4807-4818. doi: 10.21873/anticanres.14484.
The Role of the Microbiome in Cancer and Therapy Efficacy: Focus on Lung Cancer
Adrienne Halley 1 2, Alessandro Leonetti 2 3, Alessandro Gregori 2, Marcello Tiseo 3 4, Dong Mei Deng 5, Elisa Giovannetti 2 6, Godefridus J Peters 7 8
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PMID: 32878769
DOI: 10.21873/anticanres.14484

Abstract


The microbiome is extremely important for human health; more recently its role in the context of cancer became clear. Microbial effects range from enhancing cancer immunity and cancer therapy efficacy, to promoting cancer progression and inhibiting treatment efficacy. These broad implications led researchers to investigate these specific interactions, as well as how modification of the microbiome can improve cancer survival and treatment efficacy. While these interactions are better established for cancers such as gastric cancer, they are far less understood in others. As non-small cell lung cancer (NSCLC) makes up the majority of lung cancer cases, and is among the top causes of cancer deaths worldwide, understanding the mechanisms by which the microbiome may impact progression and treatment is crucial to improve patient survival and treatment response. A literature review was conducted to reveal the crosslink between human microbiome and lung cancer. This includes immune priming, induction of pro- or anti-tumor response, and the local effects of intra-tumoral microbiota. Overall, this is a complex multifactorial relationship, and there are broad implications as to how this knowledge can improve cancer treatment. Solutions include manipulation of the microbiome using probiotics, bacterial vaccines and antibiotics. Bacteria biomarkers may also be used as a diagnostic tool.

Keywords: Microbiome; cancer therapy; carcinogenesis; lung cancer; review.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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3
Review
Anticancer Res




. 2020 Sep;40(9):4843-4856. doi: 10.21873/anticanres.14487.
Inhibitors of Fatty Acid Synthesis and Oxidation as Potential Anticancer Agents in Colorectal Cancer Treatment
Paulina Mozolewska 1, Katarzyna Duzowska 1, Alicja Pakiet 2, Adriana Mika 1 2, Tomasz ŚledziŃski 3
Affiliations expand
PMID: 32878772
DOI: 10.21873/anticanres.14487

Abstract


Aberrant fatty acid (FA) metabolism has long been recognized in colorectal cancer (CRC) cells. Since de novo lipogenesis is required for CRC tumour growth and survival, the inhibition of FA metabolism is a promising potential therapeutic target. Inhibition of the opposite process, β-oxidation of FAs, has also showed promising results in many CRC models. For patients with CRC, both FA synthesis and β-oxidation inhibitors are promising potential therapeutic options as monotherapies or as combination therapies with other anticancer agents. In this review, we discuss recent reports concerning inhibitors of FA synthesis and β-oxidation in various CRC models. The exact mechanisms of action of the selected compounds described in this review remain unknown and require precise evaluation before the development of new successful therapies for CRC is possible.

Keywords: Colorectal cancer; fatty acid oxidation; fatty acid synthesis; inhibitors; review.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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4
Anticancer Res




. 2020 Sep;40(9):5001-5013. doi: 10.21873/anticanres.14503.
The Effects of Newly Synthesized Platinum(IV) Complexes on Cytotoxicity and Radiosensitization of Human Tumour Cells In Vitro
Marija Petrovic 1, Suzana Popovic 2, Dejan Baskic 2, Milos Todorovic 3, Predrag Djurdjevic 4, Aleksandra Ristic-Fira 5, Otilija Keta 5, Vladana Petkovic 5, Lela Koricanac 5, Danijela Stojkovic 6, Verica Jevtic 7, Srecko Trifunovic 7, Danijela Todorovic 8
Affiliations expand
PMID: 32878788
DOI: 10.21873/anticanres.14503

Abstract


Aim: Newly synthesized platinum(IV) complexes with ethylenediamine-N,N'-diacetate ligands (EDDA-type) (butyl-Pt and pentyl-Pt) were investigated against two cancer (A549 lung, and HTB 140 melanoma) and one non-cancerous (MRC-5 embryonic lung fibroblast) human cell lines.

Materials and methods: The effects of these agents were compared with those of cisplatin after 6-, 24- and 48-h treatment. Sulforhodamine-B (SRB) assay was performed to estimate the cytotoxic effect, while the inhibitory effect on cell proliferation was measured using 5-bromo-2,-deoxyuridine (BrdU) incorporation assay. Cell cycle analysis was performed by flow cytometry. Type of cell death induced by these agents was determined by electrophoretic analysis of DNA, flow cytometry and by western blot analysis of proteins involved in induction of apoptosis. The effects of gamma irradiation, alone and in combination with platinum-based compounds, were examined by clonogenic and SRB assays.

Results: All examined platinum-based compounds had inhibitory and antiproliferative effects on A549 cells, but not on HTB140 and MRC-5 cells. Butyl-Pt, pentyl-Pt and cisplatin arrested the cell cycle in the S-phase and induced apoptotic cell death via regulation of expression of B-cell lymphoma 2 (BCL2) and BCL2-associated X (BAX) proteins. Platinum-based compounds increased the sensitivity of A549 cells to gamma irradiation. Butyl-Pt and pentyl-Pt showed better antitumour effects against A549 cells than did cisplatin, by interfering in cell proliferation and the cell cycle, and by triggering apoptosis.

Conclusion: The effects of gamma irradiation on tumour cells may be amplified by pre-treatment of cells with platinum-based compounds.

Keywords: Apoptosis; cancer; cell cycle; cytotoxicity; gamma rays; platinum(IV) complexes.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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5
Anticancer Res




. 2020 Sep;40(9):5141-5149. doi: 10.21873/anticanres.14517.
Temozolomide and AZD7762 Induce Synergistic Cytotoxicity Effects on Human Glioma Cells
Yun Chen 1 2, Bor-Jiun Tseng 1, Ya-Hui Tsai 1 2, Sheng-Hong Tseng 3
Affiliations expand
PMID: 32878802
DOI: 10.21873/anticanres.14517

Abstract


Background/aim: This study investigated the effects of temozolomide (TMZ) and/or checkpoint kinase inhibitor AZD7762 in human glioma cells.

Materials and methods: Glioma cells were treated with TMZ and/or AZD7762 for 24 or 48 h, then the cellular survival was studied and the expression of various proteins was investigated.

Results: Both TMZ and AZD7762 induced concentration- and time-dependent cytotoxic effects, and combined TMZ and AZD7762 (TMZ+AZD) caused synergistic cytotoxic effects in glioma cells (p<0.05). AZD7762 suppressed the O6-methylguanine-DNA-methyltransferase (MGMT) expression. TMZ+AZD increased the expression of phospho-p53 (p-p53), p-p38 mitogen-activated protein kinase, and phosphatase and tensin homolog; and decreased the expression of p-extracellular signal-regulated kinase 1/2 and p-signal transducer and activator of transcription 3 in glioma cells.

Conclusion: TMZ and AZD7762 combined induced synergistic cytotoxic effects on human glioma cells and such effects may be related to the AZD7762-induced suppression of MGMT expression and the modulation of multiple signaling pathways.

Keywords: AZD7762; Temozolomide; cytotoxicity; glioma.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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6
Anticancer Res




. 2020 Sep;40(9):5159-5170. doi: 10.21873/anticanres.14519.
Redox-related Molecular Mechanism of Sensitizing Colon Cancer Cells to Camptothecin Analog SN38
Biliana Nikolova 1 2, Severina Semkova 1 2 3, Iana Tsoneva 1, Elena Stoyanova 4, Pavel Lefterov 5, Dessislava Lazarova 6, Zhivko Zhelev 1 7, Ichio Aoki 2 3, Tatsuya Higashi 3, Rumiana Bakalova 8 3 6
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PMID: 32878804
DOI: 10.21873/anticanres.14519

Abstract


Background/aim: The aim of this study was to elucidate the possibility of sensitizing colon cancer cells to the chemotherapeutic drug SN38 and investigate its mechanism of action after combined treatment with electroporation (EP).

Materials and methods: Cells were treated with SN38, EP and their combination for 24/48 h. The cell viability, actin cytoskeleton integrity, mitochondrial superoxide, hydroperoxides, total glutathione, phosphatidyl serine expression, DNA damages and expression of membrane ABC transporters were analyzed using conventional analytical tests.

Results: The combination of EP and SN38 affected cell viability and cytoskeleton integrity. This effect was accompanied by: (i) high production of intracellular superoxide and hydroperoxides and depletion of glutathione; (ii) increased DNA damage and apoptotic/ferroptotic cell death; (iii) changes in the expression of membrane ABC transporters - up-regulation of SLCO1B1 and retention of SN38 in the cells.

Conclusion: The anticancer effect of the combined treatment of SN38 and EP is related to changes in the redox-homeostasis of cancer cells, leading to cell death via apoptosis and/or ferroptosis. Thus, electroporation has a potential to increase the sensitivity of cancer cells to conventional anticancer therapy with SN38.

Keywords: Colorectal cancer; SN38; electroporation; ferroptosis; multidrug resistance; oxidative stress; redox-status.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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7
Anticancer Res




. 2020 Sep;40(9):4989-4999. doi: 10.21873/anticanres.14502.
Ephemeranthol A Suppresses Epithelial to Mesenchymal Transition and FAK-Akt Signaling in Lung Cancer Cells
Nongyao Nonpanya 1 2, Ornjira Prakhongcheep 1 2, Korrakod Petsri 1 2, Cholasit Jitjaicham 2, Sucharat Tungsukruthai 1 2, Boonchoo Sritularak 3, Pithi Chanvorachote 4 2
Affiliations expand
PMID: 32878787
DOI: 10.21873/anticanres.14502

Abstract


Background/aim: Epithelial to mesenchymal transition (EMT) is a cellular process that facilitates cancer metastasis. Therefore, therapeutic approaches that target EMT have garnered increasing attention. The present study aimed to examine the in vitro effects of ephemeranthol A on cell death, migration, and EMT of lung cancer cells.

Materials and methods: Ephemeranthol A was isolated from Dendrobium infundibulum. Non-small cell lung cancer cells H460 were treated with ephemeranthol A and apoptosis was evaluated by Hoechst 33342 staining. Anoikis resistance was determined by soft agar assay. Wound healing assay was performed to test the migration. The regulatory proteins of apoptosis and cell motility were determined by western blot.

Results: Treatment with ephemeranthol A resulted in a concentration-dependent cell apoptosis. At non-toxic concentrations, the compound could inhibit anchorage-independent growth of the cancer cells, as indicated by the decreased colony size and number. Ephemeranthol A also exhibited an inhibitory effect on migration. We further found that ephemeranthol A exerts its antimetastatic effects via inhibition of EMT, as indicated by the markedly decrease of N-cadherin, vimentin, and Slug. Furthermore, the compound suppressed the activation of focal adhesion kinase (FAK) and protein kinase B (Akt) proteins, which are key regulators of cell migration. As for the anticancer activity, ephemeranthol A induced apoptosis by decreasing Bcl-2 followed by the activation of caspase 3 and caspase 9.

Conclusion: The pro-apoptotic and anti-migratory effects of ephemeranthol A on human lung cancer cells support its use for the development of novel anticancer therapies.

Keywords: Ephemeranthol A; apoptosis; epithelial to mesenchymal transition (EMT); lung cancer.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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8
Anticancer Res




. 2020 Sep;40(9):5191-5200. doi: 10.21873/anticanres.14522.
Methylsulfonylmethane Induces Cell Cycle Arrest and Apoptosis, and Suppresses the Stemness Potential of HT-29 Cells
Doh Hoon Kim 1, Dong Young Kang 1, Nipin Sp 1, Eun Seong Jo 1, Alexis Rugamba 1, Kyoung-Jin Jang 2, Young Mok Yang 2
Affiliations expand
PMID: 32878807
DOI: 10.21873/anticanres.14522

Abstract


Background/aim: Colorectal cancer is one of the most common malignancies worldwide. Small molecule-based chemotherapy is an attractive approach for the chemoprevention and treatment of colorectal cancer. Methylsulfonylmethane (MSM) is a natural organosulfur compound with anticancer properties, as revealed by studies on in vitro models of gingival, prostate, lung, hepatic, and breast cancer. However, the molecular mechanisms underlying the effects of MSM in colon cancer cells remain unclear.

Materials and methods: Here, we investigated the effects of MSM, especially on the cell cycle arrest and apoptosis, in HT-29 cells.

Results: MSM suppressed the viability of HT-29 cells by inducing apoptosis and cell cycle arrest at the G0/G1 phase. MSM suppressed the sphere-forming ability and expression of stemness markers in HT-29 cells.

Conclusion: MSM has anti-cancer effects on HT-29 cells, and induces cell cycle arrest and apoptosis, while suppressing the stemness potential.

Keywords: HT-29 cells; Methylsulfonylmethane; apoptosis; cell cycle arrest; stemness.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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9
Anticancer Res




. 2020 Sep;40(9):5059-5069. doi: 10.21873/anticanres.14509.
Cetyltrimethylammonium Bromide Suppresses the Migration and Invasion of Hepatic Mahlavu Cells by Modulating Fibroblast Growth Factor Signaling
Tsai-Kun Wu 1 2, Chung-Hung Chen 3, Wei-Ting Lee 4, Tzu-Fen Su 5, Ying-Ru Pan 6, Fu-Mei Huang 7, Chia-Jen Lee 8 9
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PMID: 32878794
DOI: 10.21873/anticanres.14509

Abstract


Background/aim: Liver cancer is the fourth leading cause of cancer-related mortality globally, of which hepatocellular carcinoma (HCC) accounts for 85-90% of total primary liver cancer. A drug shortage for HCC therapy triggered us to screen the small-molecule database with a high-throughput cellular screening system. Herein, we examined whether cetyltrimethylammonium bromide (CTAB) inhibits cellular mobility and invasiveness of Mahlavu HCC cells.

Materials and methods: The effects of CTAB on cell viability were assessed using WST-1 assay, cell-cycle distribution using flow cytometric analysis, migration/invasion using woundhealing and transwell assays, and associated protein levels using western blotting.

Results: Treatment of Mahlavu cells with CTAB transformed its mesenchymal spindle-like morphology. In addition, CTAB exerted inhibitory effects on the migration and invasion of Mahlavu cells dose-dependently. CTAB also reduced the protein levels of matrix metalloproteinase-2 (MMP2), MMP9, RAC family small GTPase 1, SNAIL family transcriptional repressor 1 (SNAI1), SNAI2, TWIST family basic helix-loop-helix transcription factor 1 (TWIST1), vimentin, N-cadherin, phospho-fibroblast growth factor (FGF) receptor, phospho-phosphoinositide 3-kinase, phospho-v-Akt murine thymoma viral oncogene and phospho-signal transducer and activator of transcription 3 but increased the protein levels of tissue inhibitor of metalloproteinases-1/2 and E-cadherin. Rescue experiments proved that CTAB induced mesenchymal-epithelial transition in Mahlavu cells and this was significantly dose-dependently mitigated by basic FGF.

Conclusion: CTAB suppressed the migration and invasion of Mahlavu cells through inhibition of the FGF signaling pathway. CTAB seems to be a potential agent for preventing metastasis of hepatic cancer.

Keywords: CTAB; Cetyltrimethylammonium bromide; FGF; Mahlavu; fibroblast growth factor; hepatic cancer.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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10
Published Erratum
Anticancer Res




. 2020 Sep;40(9):5327.
Erratum
No authors listed
PMID: 32878825
No abstract available

Erratum for
Geographical Differences in Likelihood of Home Death Among Palliative Cancer Patients: A National Population-based Register Study.
Nilsson J, Axelsson B, Holgersson G, Carlsson T, Bergqvist M, Bergstrom S.Anticancer Res. 2020 Jul;40(7):3897-3903. doi: 10.21873/anticanres.14380.PMID: 32620630
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11
Anticancer Res




. 2020 Sep;40(9):5125-5140. doi: 10.21873/anticanres.14516.
Anti-progressive Effects of a Series of Glycinyl and Alaninyl Triazolyl-oxazolidinones on Kelly Neuroblastoma Cell Line
Nada A Al-Hasawi 1, Oludotun A Phillips 2, Fatma Al-Awadhi 2, Leyla H Sharaf 2, Sanaa A Amine 2, Ladislav Novotny 2
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PMID: 32878801
DOI: 10.21873/anticanres.14516

Abstract


Background/aim: Neuroblastoma (NB), the most common extracranial malignant childhood tumor accounts for about 15% of cancer-related deaths in children. Despite the intensive treatment of patients with high-risk scarification of NB, clinical outcomes indicate tumor recurrence greater than 50% and late severe adverse effects. Oxazolidinones are 5-membered heterocyclic compounds with antibacterial activity against resistant bacterial strains. Structural modifications around the oxazolidinone moiety have resulted in derivatives with anti-cancer properties against proliferation, motility, and invasion of breast cancer cells. This study aimed to examine the anti-cancer potential of novel oxazolidinones against a model of a neuroblastoma cell line.

Materials and methods: Newly synthesized and characterized triazolyl-oxazolidinone derivatives were incubated with neuroblastoma Kelly cells. The anti-proliferation and anti-progression effects of the compounds were evaluated by MTT, and adhesion with migration assays.

Results: The 5-nitrofuroyl glycinyl-oxazolidinone containing 4-methyltriazolyl group demonstrated the most potent activity with an IC50=6.52 μM. Furthermore, the D-isomer of 5-nitrothiophenecarbonyl alaninyl containing derivative reduced the adhesion to fibronectin by 56.34%, while the D-isomer of 5-nitrofuroyl alaninyl derivative reduced the migration of Kelly cells by 29.14%.

Conclusion: The presence of the 4-methyltriazolyl moiety seems to enhance the anti-proliferative property of triazolyl-oxazolidinone derivatives, as demonstrated by PH-145. There is little or no effect of the stereochemistry of the alanine side-chain on the antiproliferative effect, as demonstrated by the 5-nitrofuroyl D- and L-alaninyl containing derivatives with similar IC50 values. The observed differences in the inhibition of adhesion and migration by the oxazolidinones on Kelly cells provide a new therapeutic approach that needs further investigation.

Keywords: BSA heat denaturation; Kelly cell line; Oxazolidinones; adhesion; fibronectin; neuroblastoma; progression; proliferation.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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12
Anticancer Res




. 2020 Sep;40(9):5025-5033. doi: 10.21873/anticanres.14505.
A New Ciprofloxacin-derivative Inhibits Proliferation and Suppresses the Migration Ability of HeLa Cells
Moustafa Fathy 1 2, Sijia Sun 3, Qing-Li Zhao 4, Mohamed Abdel-Aziz 5, Gamal El-Din A Abuo-Rahma 5, Suresh Awale 3, Toshio Nikaido 1
Affiliations expand
PMID: 32878790
DOI: 10.21873/anticanres.14505

Abstract


Background/aim: This study aimed to investigate the effect of a new 7-(4-(N-substituted carbamoylmethyl) piperazin-1-yl) ciprofloxacin-derivative on the proliferation and migration abilities of HeLa cells.

Materials and methods: Cell viability and morphological alterations were examined. Changes in migration were detected using wound healing and colony formation assays. Flow cytometry and western blotting were used to investigate the molecular mechanisms underlying this ciprofloxacin-derivative's action in HeLa cells.

Results: The examined ciprofloxacin-derivative reduced viability of HeLa cells in a concentration-dependent manner and altered cellular morphology, indicating cell death. Furthermore, it significantly inhibited wound closure, even in a non-cytotoxic concentration, and reduced HeLa cell colony formation. In addition, apoptosis was increased probably through significant up-regulation of Bax protein expression and the generation of active cleaved caspase-3 protein.

Conclusion: Our new derivative inhibits proliferation and induces apoptosis of HeLa cells. Furthermore, it suppressed the migration and colony formation abilities of HeLa cells. Therefore, it represents an attractive agent for drug development against cervical cancer based on its anti-metastatic effect.

Keywords: Apoptosis; HeLa cells; ciprofloxacin; colony formation; migration ability.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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13
Anticancer Res




. 2020 Sep;40(9):4875-4883. doi: 10.21873/anticanres.14490.
A Potential Mechanism of Anticancer Immune Response Coincident With Immune-related Adverse Events in Patients With Renal Cell Carcinoma
Taigo Kato 1 2, Eisuke Tomiyama 3, Yoko Koh 3, Makoto Matsushita 3, Yujiro Hayashi 3, Kosuke Nakano 3, Y U Ishizuya 3, Cong Wang 3, Koji Hatano 3, Atsunari Kawashima 3, Takeshi Ujike 3, Keisuke Kawasaki 4, Eiichi Morii 4, Kunihito Gotoh 5, Hidetoshi Eguchi 5, Kazuma Kiyotani 6, Kazutoshi Fujita 3, Norio Nonomura 3, Motohide Uemura 3 2
Affiliations expand
PMID: 32878775
DOI: 10.21873/anticanres.14490

Abstract


Background/aim: Some reports showed encouraging efficacy of immune checkpoint inhibitors among patients who experienced immune-related adverse events (irAEs). Thus, characterization of T-cell repertoire and immune signatures in peripheral blood mononuclear cells (PBMCs) and tumors before and after immune checkpoint inhibitors treatment should contribute to better understanding of irAE-provoked anticancer immune responses.

Materials and methods: We applied expression analysis of immune-related genes and T-cell receptor sequencing in tumor and PBMCs from five patients with renal cell carcinoma before combined immunotherapy and at the onset of severe irAEs.

Results: We found that the cluster of differentiation 8 (CD8)/forkhead box P3(FOXP3), granzyme B(GZMB)/CD3, perforin 1(PRF1)/CD3 and programmed cell death 1(PD1)/CD8 expression ratios were significantly elevated in PBMCs at the onset of irAEs. In addition, we found expansion of certain T-cell clones in metastatic tissue after irAEs, which were already increased in peripheral blood at the onset of irAEs.

Conclusion: irAE-provoked T-cells may also circulate and attack distant tumors, leading to durable response in patients with irAEs.

Keywords: Immune checkpoint inhibitors; T-cell receptor; immune response; immune-related adverse events (irAEs); next-generation sequencing; renal cell carcinoma.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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14
Anticancer Res




. 2020 Sep;40(9):4947-4960. doi: 10.21873/anticanres.14498.
Effects of Sclareol Against Small Cell Lung Carcinoma and the Related Mechanism: In Vitro and In Vivo Studies
Hsiang Lai Chen 1 2, Jiny Yin Gong 3, Shih-Chao Lin 4 5, Shiming Li 6, Yu-Chih Chiang 7, Jui-Hsiang Hung 8, Chieh-Chi Yen 9, Chi-Chien Lin 10 3 11 12
Affiliations expand
PMID: 32878783
DOI: 10.21873/anticanres.14498

Abstract


Background/aim: This study aimed to investigate the anticancer effects and potential mechanisms of sclareol in a human small cell lung carcinoma (SCLC) cell line.

Materials and methods: Cell viability was determined by the MTT assay. Cell cycle, apoptosis and caspase activity were evaluated by flow cytometry. Cell cycle and DNA damage related protein expression was determined by western blotting. In vivo evaluation of sclareol was carried out in xenografted tumor mice models.

Results: Sclareol significantly reduced cell viability, induced G1 phase arrest and subsequently triggered apoptosis in H1688 cells. In addition, this sclareol-induced growth arrest was associated with DNA damage as indicated by phosphorylation of H2AX, activation of ATR and Chk1. Moreover, in vivo evaluation of sclareol showed that it could inhibit tumor weight and volume in a H1688 xenograft model.

Conclusion: Sclareol might be a novel and effective therapeutic agent for the treatment of SCLC patients.

Keywords: DNA damage; Sclareol; Small cell lung carcinoma; apoptosis; cell cycle; xenograft.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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15
Anticancer Res




. 2020 Sep;40(9):5107-5114. doi: 10.21873/anticanres.14514.
Anti-tumor Effect of Hedgehog Signaling Inhibitor, Vismodegib, on Castration-resistant Prostate Cancer
Aya Ishii 1, Katsumi Shigemura 2 3, Koichi Kitagawa 1 4, Shian-Ying Sung 5, Kuan-Chou Chen 6, Chiang Yi-Te 6, Ming-Che Liu 6, Masato Fujisawa 3
Affiliations expand
PMID: 32878799
DOI: 10.21873/anticanres.14514

Abstract


Background/aim: Epithelial-mesenchymal transition (EMT) via Sonic Hedgehog (Shh) signaling may be one of the mechanisms of progression of castration-resistant prostate cancer (CRPC). In this study, we investigated the possible therapeutic effect of vismodegib, a new Shh inhibitor, in a mouse CRPC model.

Materials and methods: We determined cell proliferation, apoptosis and the expression of EMT-related genes for three prostate cancer cell lines; androgen-dependent LNCaP and independent C4-2B and PC-3 in the presence of vismodegib in vitro. Fifty mg/kg of vismodegib were orally administered into mice bearing C4-2B and PC-3 tumors, respectively every other week for 3 weeks.

Results: Vismodegib significantly inhibited cell proliferation and induced cell apoptosis in all cell lines in vitro (p<0.05). Vismodegib significantly inhibited EMT in CRPC cells and tumor growth in C4-2B-bearing mice compared to controls in vivo (p<0.05). Higher expression of caspase-3 and lower expression of vimentin in PC-3 and C4-2B tumors were induced by vismodegib in immunohistochemical analysis.

Conclusion: Vismodegib inhibited cell proliferation via apoptosis and also suppressed EMT, showing anti-tumor effects in mice. Further mechanistic studies are needed to investigate the feasibility of vismodegib for CRPC treatment.

Keywords: Hedgehog signaling; Sonic hedgehog; Vismodegib; castration-resistant prostate cancer; epithelial-mesenchymal transition.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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16
Anticancer Res




. 2020 Sep;40(9):5081-5090. doi: 10.21873/anticanres.14511.
Novel Imidazo[2,1-b]oxazole Derivatives Inhibit Epithelial Cell Transformation and Triple Negative Breast Cancer Tumorigenesis
Poshan Yugal Bhattarai 1, Chang-Hyun Oh 2, Garam Kim 1, Min Soo Kim 1, Bong Sang Lee 3, Hong Seok Choi 4
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PMID: 32878796
DOI: 10.21873/anticanres.14511

Abstract


Background/aim: Triple negative breast cancer (TNBC) is an aggressive type of breast cancer with limited targets for chemotherapy. This study evaluated the inhibitory effects of novel imidazo[2,1-b]oxazole-based rapidly accelerated fibrosarcoma (RAF) inhibitors, KIST0215-1 and KIST0215-2, on epithelial cell transformation and TNBC tumorigenesis.

Materials and methods: Immunoblotting, BrdU incorporation assay, reporter gene assay, and soft agar assay analyses were performed. In vivo effects were studied using the BALB/c mouse xenograft model.

Results: KIST0215-1 and KIST0215-2 inhibited the RAFs-MEK1/2-ERK1/2 signalling pathway induced by EGF in MDA-MB-231 cells, which inhibited c-fos transcriptional activity and activator protein-1 transactivation activity. KIST0215-1 and KIST0215-2 also prevented neoplastic transformation of JB6 C141 mouse epidermal cells induced by EGF and consistently suppressed the growth of tumours formed by 4T1 cells in BALB/c mice.

Conclusion: Inhibition of RAF kinases using KIST0215-1 and KIST0215-2 is a promising chemotherapeutic strategy to treat TNBC.

Keywords: Imidazo[2,1-b]oxazole derivatives; RAF inhibitors; TNBC; chemotherapy.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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17
Anticancer Res




. 2020 Sep;40(9):5291-5294. doi: 10.21873/anticanres.14534.
Severe Gastrointestinal Mucositis Following Concurrent Palbociclib and Palliative Radiation Therapy
Umair M Nasir 1, Alexander M Mozeika 2, Mutlay Sayan 3, Imraan Jan 3, Noel Kowal 4, Bruce Haffty 3, Sushil Ahlawat 5, Neil Kothari 2
Affiliations expand
PMID: 32878819
DOI: 10.21873/anticanres.14534

Abstract


Background/aim: Palbociclib is an FDA-approved cyclin-dependent kinase inhibitor for the treatment of advanced breast cancer. Limited information is available regarding the toxicity of palbociclib and concurrent radiation therapy.

Case report: Herein, we report a case of esophageal toxicity in a patient treated with palbociclib and radiation therapy. A 63-year-old woman was treated with palbociclib followed by palliative radiation therapy. The patient presented three days after completing radiation therapy with severe odynophagia, and dysphagia and was found to have grade 2-3 esophageal ulcers. Palbociclib and radiation therapy was held on admission, and a resolution of her symptoms and improvement in her oral intake was noted at which time she was restarted on palbociclib with no further radiation treatment.

Conclusion: Caution is advised when patients are undergoing concurrent palbociclib and even low-dose palliative radiation treatment. In these patients, providers should maintain a high index of suspicion for toxicities such as dermatitis or mucositis.

Keywords: Ibrance; Mucositis; chemoradiation; chemotherapy; palbociclib; palliative; radiation therapy.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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18
Anticancer Res




. 2020 Sep;40(9):5015-5024. doi: 10.21873/anticanres.14504.
Assessment of In Vitro Anti-melanoma Potential of Ephedranthus pisocarpus R.E.Fr
Lubna Karine Beserra Santos 1, MÁrcia Denise Alves Veras 2, Karinne Kelly Gadelha Marques 3, Michel MualÉm DE Moraes Alves 1 4, Anderson Nogueira Mendes 5, Fernando AÉcio DE Amorim Carvalho 1, Marianna Vieira Sobral 3, Mariana Helena Chaves 2, Juan Carlos Ramos GonÇalves 6 3
Affiliations expand
PMID: 32878789
DOI: 10.21873/anticanres.14504

Abstract


Background/aim: Despite being a rare disease, melanoma is considered the most dangerous skin cancer due to its highly invasive and aggressive nature, and still requires for more effective treatments. The aim of this study was to evaluate the in vitro anti-melanoma potential of Ephedranthus pisocarpus R.E.Fr. (Annonaceae), a popular Brazilian plant with medicinal properties.

Materials and methods: Initially, the ethanolic extract (EtOH) was obtained from E. pisocarpus leaves and later partitioned using increasing polarity solvents. The anti-melanoma potential of E. pisocarpus was assessed by spectrophotometry and its cytotoxicity determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and confocal microscopy.

Results: We demonstrated that the EtOH extract and fractions from E. pisocarpus had a moderate photoprotective action (FPS 3.0-5.0) against UVA radiation. Interestingly, the dichloromethane fraction presented higher anti-melanoma activity against B16-F10 (IC50=46.8 μg/ml) and SK-MEL-28 cells (IC50=40.1 μg/ml) and lesser toxicity on normal cells. Additionally, our study reported that spathulenol, one of the major constituents from E. pisocarpus, acts through an apoptosis-dependent mechanism in SK-MEL-28 cells.

Conclusion: The present study demonstrated, for the first time, the in vitro anti-melanoma potential of E. pisocarpus against melanoma cells.

Keywords: E. pisocarpus; Melanoma; apoptosis; natural products; photoprotection; spathulenol.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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19
Anticancer Res




. 2020 Sep;40(9):4969-4978. doi: 10.21873/anticanres.14500.
Brucea javanica Increases Survival and Enhances Gemcitabine Efficacy in a Patient-derived Orthotopic Xenograft (PDOX) Mouse Model of Pancreatic Cancer
Haitao Yang 1 2 3, Zhong Tong 1 2 3, Lei Shen 4, Y U Sun 5 6, Robert M Hoffman 5 6, Jun Huang 7 2 3
Affiliations expand
PMID: 32878785
DOI: 10.21873/anticanres.14500

Abstract


Background/aim: Traditional Chinese medicine (TCM) Brucea javanica (BJO) has shown anti-proliferation efficacy on human carcinoma cells in vitro. The aim of the present study was to evaluate for the first time the efficacy of BJO combined with the first-line chemotherapeutic drug gemcitabine (GEM) on tumor growth-inhibition and survival in a pancreatic cancer patient-derived orthotopic xenograft (PDOX) mouse model.

Materials and methods: The pancreatic cancer tumor fragment originated from a patient at the Hefei First People's Hospital (Anhui, PR China). The surgical specimen was transplanted orthotopically in nude mice using surgical orthotopic implantation (SOI). All mice were randomized and assigned to 5 groups: G1: saline vehicle (0.1ml per mouse, oral, once per day); G2: GEM [100 mg/kg, intraperitoneal (i.p), twice per week]; G3: GEM+BJO [100 mg/kg GEM, i.p, twice per week+1g/kg BJO, oral, once per day (qd)]; G4: BJO (1g/kg, oral, qd). Group 5 and Group 6 were used to observe survival [G5: saline vehicle (0.1ml per mouse, oral, qd), G6: BJO (1g/kg, oral, qd)]. Body weight and tumor volume were measured twice per week. TUNEL staining was used to determine apoptosis.

Results: The combination of GEM + BJO resulted in a reduced tumor growth rate (p<0.05) and greater apoptosis (p<0.05) compared to the vehicle control and GEM monotherapy. In addition, the BJO-treated group showed a statistically significant increase in survival compared to the vehicle control (p<0.05).

Conclusion: BJO is a promising non-toxic TCM to effectively treat pancreatic cancer, both as monotherapy and in combination with first-line GEM therapy.

Keywords: Brucea javanica; PDOX; Pancreatic cancer; combination therapy; gemcitabine; survival; synergistic effect.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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20
Anticancer Res




. 2020 Sep;40(9):5271-5276. doi: 10.21873/anticanres.14531.
Factors Raising Serum Ammonia Level During Lenvatinib Treatment of Patients With Hepatocellular Carcinoma
Ryoichi Narita 1 2, Kazuhiro Kotoh 3, Akitoshi Yoneda 4 2, Mitsuteru Motomura 4, Masaru Harada 2
Affiliations expand
PMID: 32878816
DOI: 10.21873/anticanres.14531

Abstract


Background/aim: Hepatic encephalopathy is an adverse event resulting from lenvatinib use in patients with hepatocellular carcinoma (HCC). We analyzed the influence of lenvatinib on portal venous flow velocity (PVV) and serum ammonia concentration.

Patients and methods: Eleven patients with unresectable HCC were enrolled, including three with modified albumin-bilirubin (mALBI) grade 1, three with grade 2a, and five with grade 2b. PVV was measured by Doppler ultrasound sonography before and on day 2 of administration.

Results: Out of 11 patients, one developed hepatic encephalopathy. PVV was reduced in 10 patients, and the change from baseline was significantly correlated with lenvatinib dosage. The increase in serum ammonia concentration was affected by lenvatinib dose and baseline hepatic function as a threshold between mALBI grade 2a and 2b statistically. There was no correlation between changes in PVV and serum ammonia concentration.

Conclusion: Lenvatinib might directly disturb hepatocyte metabolism to result in increased serum ammonia concentration.

Keywords: Hepatocellular carcinoma; hepatic encephalopathy; lenvatinib; portal vein flow velocity.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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21
Anticancer Res




. 2020 Sep;40(9):4979-4987. doi: 10.21873/anticanres.14501.
CDKN1A Gene Expression in Two Multiple Myeloma Cell Lines With Different P53 Functionality
Denisa Hrckova Drozdkova 1 2, Jan Gursky 3, Jiri Minarik 4 5, Ivo Überall 6, Zdenek Kolar 6 4, Katerina Smesny Trtkova 1 2
Affiliations expand
PMID: 32878786
DOI: 10.21873/anticanres.14501

Abstract


Background/aim: Multiple myeloma is a highly heterogeneous disease of clonal plasma cells. Histone deacetylase (HDAC) inhibitors are promising anticancer drugs but their precise mechanisms of actions are not well understood.

Materials and methods: Cell-cycle regulation and pro-apoptotic effects of two histone deacetylase inhibitors, suberohydroxamic acid (SAHA) and suberoylanilide hydroxamic acid (SBHA), were analyzed in multiple myeloma cell lines RPMI8226 and U266 with differing TP53 status using gene-expression analysis.

Results: Enhanced expression of cyclin-dependent kinase inhibitor 1A (CDKN1A/p21WAF/CIP1) detected in the TP53-deleted U266 cell line after SAHA treatment indicates the P53-independent mode of transcriptional activation of CDKN1A gene. In contrast, CDKN1A gene expression was significantly increased by both SBHA and SAHA treatment of TP53-mutated RPMI8226 cells.

Conclusion: SAHA appears to be a potentially effective pro-apoptotic and anticancer drug with universal application in the treatment of heterogeneous populations of multiple myeloma cells.

Keywords: Multiple myeloma; apoptosis; gene expression; myeloma cell lines.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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22
Anticancer Res




. 2020 Sep;40(9):5071-5079. doi: 10.21873/anticanres.14510.
Setanaxib as a Potent Hypoxia-specific Therapeutic Agent Against Liver Cancer
Satoshi Owada 1, Hitoshi Endo 2, Chisa Okada 3, Kazuhiro Yoshida 3, Yukari Shida 2, Masayuki Tatemichi 2
Affiliations expand
PMID: 32878795
DOI: 10.21873/anticanres.14510

Abstract


Background/aim: Liver cancer has extremely poor prognosis. The cancerous tissues contain hypoxic regions, and the available drugs are poorly effective in hypoxic environments. NADPH oxidase 4 (NOX4), producing reactive oxygen species (ROS), may contribute to cancer malignancy under hypoxic conditions. However, its role in liver cancer has not been examined in detail. Our aim was to explore the effects of setanaxib, a recently developed selective NOX4 inhibitor, in liver cancer cells under hypoxic conditions.

Materials and methods: Liver cancer cell lines (HepG2, HLE and Alexander) were treated with hypoxia-mimetic agent cobalt chloride. Cytotoxicity assays, immunoblot analysis and ROS detection assay were performed to detect the effect of setanaxib under hypoxic conditions.

Results: Setanaxib exhibited hypoxia-selective cytotoxicity and triggered apoptosis in cancer cells. Moreover, setanaxib caused mitochondrial ROS accumulation under hypoxic conditions. Treatment with antioxidants markedly attenuated setanaxib-induced cytotoxicity and apoptosis under hypoxic conditions.

Conclusion: Setanaxib caused mitochondrial ROS accumulation in a hypoxia-selective manner and evoked cancer cell cytotoxicity by inducing apoptosis. Thus, setanaxib has a great potential as a novel anticancer compound under hypoxic conditions.

Keywords: Cancer treatment; hypoxia; liver cancer; oxidative stress; setanaxib.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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23
Review
Anticancer Res




. 2020 Sep;40(9):4829-4841. doi: 10.21873/anticanres.14486.
The Future of ER+/HER2- Metastatic Breast Cancer Therapy: Beyond PI3K Inhibitors
Athina Stravodimou 1, Ioannis A Voutsadakis 2 3
Affiliations expand
PMID: 32878771
DOI: 10.21873/anticanres.14486

Abstract


Most breast cancers express the estrogen receptor (ER) receptor and are negative for the human epidermal growth factor receptor 2 (HER2) receptor. ER+/HER2- cancers are treated with hormone-based therapies in the adjuvant setting and derive significant survival benefit from these therapies in the metastatic setting. However, hormone resistance develops in most metastatic patients. An increased understanding of the biology of ER+/HER2- breast cancers has led to the development of new therapies for this disease including CDK4/6 inhibitors and PI3K inhibitors. Several other neoplastic processes are targeted by novel drugs in clinical development, addressing cancer vulnerabilities. These include newer ways to block the ER and targeting the HER2 receptors in ER+/HER2- cancers expressing HER2 in low levels not qualifying for clinical positivity. In addition, promising therapeutic options include targeting other surface receptors or their downstream pathways, as well as targeting the apoptotic machinery and boosting the immune response which is initially insufficient in these cancers. A selection of new drugs in advanced development for ER+/HER2- breast cancer will be discussed in this review.

Keywords: ER positive; ER targeting; FGFR inhibitors; breast cancer; elacestrant; review; venetoclax.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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24
Anticancer Res




. 2020 Sep;40(9):4857-4867. doi: 10.21873/anticanres.14488.
Targeting Membrane HDM-2 by PNC-27 Induces Necrosis in Leukemia Cells But Not in Normal Hematopoietic Cells
Anusha Thadi 1, Lauren Lewis 1, Eve Goldstein 1, Anshu Aggarwal 1, Marian Khalili 1, Lindsay Steele 1, Boris Polyak 1, Shabnam Seydafkan 2, Martin H Bluth 3, Kristine A Ward 4, Michael Styler 5, Paul M Campbell 6, Matthew R Pincus 7, Wilbur B Bowne 8 9
Affiliations expand
PMID: 32878773
DOI: 10.21873/anticanres.14488

Abstract


Background/aim: Anticancer peptide PNC-27 binds to HDM-2 protein on cancer cell membranes inducing the formation of cytotoxic transmembrane pores. Herein, we investigated HDM-2 membrane expression and the effect of PNC-27 treatment on human non-stem cell acute myelogenous leukemia cell lines: U937, acute monocytic leukemia; OCI-AML3, acute myelomonocytic leukemia and HL60, acute promyelocytic leukemia.

Materials and methods: We measured cell surface membrane expression of HDM-2 using flow cytometry. Cell viability was assessed using MTT assay while direct cytotoxicity was measured by lactate dehydrogenase (LDH) release and induction of apoptotic markers annexin V and caspase-3.

Results: HDM-2 is expressed at high levels in membranes of U937, OCI-AML3 and HL-60 cells. PNC-27 can bind to membrane HDM-2 to induce cell necrosis and LDH release within 4 h.

Conclusion: Targeting membrane HDM-2 can be a potential strategy to treat leukemia. PNC-27 targeting membrane HDM-2 demonstrated significant anti-leukemia activity in a variety of leukemic cell lines.

Keywords: Cancer cell membrane; HDM-2; PNC-27; leukemia.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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25
Anticancer Res




. 2020 Sep;40(9):5301-5307. doi: 10.21873/anticanres.14536.
Phase I Study of the Administration of Low-dose Perioperative Human Atrial Natriuretic Peptide in Patients With Resectable Colorectal Cancer
Hidekazu Takahashi 1, Takashi Takeda 2, Yujiro Nishizawa 2, Takayuki Ogino 2, Norikatsu Miyoshi 2, Chu Matsuda 2, Hirofumi Yamamoto 2, Tsunekazu Mizushima 2, Yuichiro Doki 2, Hidetoshi Eguchi 2
Affiliations expand
PMID: 32878821
DOI: 10.21873/anticanres.14536

Abstract


Background/aim: The aim of this single center, non-randomized, open-label, uncontrolled, interventional trial was to determine the feasibility of continuous administration of low-dose human atrial natriuretic peptide (hANP) perioperatively during curative operation for colorectal cancer patients without history of acute heart failure.

Patients and methods: The study included three males and two females ranging from 27 to 70 years old. Continuous intravenous injection of hANP solution was started before surgery. The primary endpoint was safety of hANP administration, and the secondary endpoints were perioperative changes in ANP, b-type natriuretic peptide, electrocardiogram (ECG), and lung function.

Results: The American Society of Anaesthesiologists physical status was 1, 2, and 3 in three, one, and one patient, respectively. Grade 2 hypotension was observed in one case. No marked changes were observed between pre- and post-operation in all cases.

Conclusion: Perioperative low-dose hANP administration is feasible and safe in patients with curative colorectal cancer.

Keywords: Colorectal cancer; feasibility; human natriuretic peptide; prevention of metastasis.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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26
Anticancer Res




. 2020 Sep;40(9):4913-4919. doi: 10.21873/anticanres.14494.
New Imidazo[2,1- b][1,3,4]Thiadiazole Derivatives Inhibit FAK Phosphorylation and Potentiate the Antiproliferative Effects of Gemcitabine Through Modulation of the Human Equilibrative Nucleoside Transporter-1 in Peritoneal Mesothelioma
Giovanna Li Petri 1 2, Camilla Pecoraro 1 2, Ornella Randazzo 1 2, Silvia Zoppi 1 3, Stella Maria Cascioferro 2, Barbara Parrino 2, Daniela Carbone 1 2, Btissame El Hassouni 1, Andrea Cavazzoni 3, Nadia Zaffaroni 4, Girolamo Cirrincione 2, Patrizia Diana 2, Godefridus J Peters 5 6, Elisa Giovannetti 1 7
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PMID: 32878779
DOI: 10.21873/anticanres.14494

Abstract


Background/aim: A new class of imidazo[2,1-b][1,3,4]thiadiazole compounds have recently been evaluated as inhibitors of phosphorylation of focal adhesion kinase (FAK) in pancreatic cancer. FAK is overexpressed in mesothelioma and has recently emerged as an interesting target for the treatment of this disease.

Materials and methods: Ten imidazo[2,1-b][1,3,4]thiadiazole compounds characterized by indole bicycle and a thiophene ring, were evaluated for their cytotoxic activity in two primary cell cultures of peritoneal mesothelioma, MesoII and STO cells.

Results: Compounds 1a and 1b showed promising antitumor activity with IC50 values in the range of 0.59 to 2.81 μM in both cell lines growing as monolayers or as spheroids. Their antiproliferative and antimigratory activity was associated with inhibition of phospho-FAK, as detected by a specific ELISA assay in STO cells. Interestingly, these compounds potentiated the antiproliferative activity of gemcitabine, and these results might be explained by the increase in the mRNA expression of the key gemcitabine transporter human equilibrative nucleoside transporter-1 (hENT-1).

Conclusion: These promising results support further studies on new imidazo[2,1-b][1,3,4]thiadiazole compounds as well as on the role of both FAK and hENT-1 modulation in order to develop new drug combinations for peritoneal mesothelioma.

Keywords: FAK; Mesothelioma; gemcitabine; human equilibrative nucleoside transporter-1; imidazo[2,1-b][1,3,4]thiadiazole compounds.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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27
Anticancer Res




. 2020 Sep;40(9):5295-5299. doi: 10.21873/anticanres.14535.
Randomized Study of Postoperative Single Intravesical Instillation With Pirarubicin and Mitomycin C for Low-risk Bladder Cancer
Shinya Yamamoto 1, Yukio Kageyama 2, Yasuhisa Fujii 3, Taku Aizawa 4, Shinji Urakami 3, Iwao Fukui 3
Affiliations expand
PMID: 32878820
DOI: 10.21873/anticanres.14535

Abstract


Background: To assess the prophylactic efficacy of postoperative single intravesical instillation with pirarubicin (THP) and mitomycin C (MMC) for low-risk non-muscle-invasive bladder cancer (NMBC).

Patients and methods: A total of 103 clinically low-risk NMBC patients were preoperatively randomized into either THP (n=49) or MMC (n=54) groups. The primary endpoint was recurrence-free survival.

Results: The median follow-up periods of the THP and MMC groups were 955 and 1008 days, respectively (p=0.76). Twelve patients (24.5%) in the THP group and 7 (13%) in the MMC group had bladder cancer recurrences. The two-year recurrence-free survival of the THP group and the MMC group was 77.8% and 86.4%, respectively (p=0.20). Neither groups had severe toxicity.

Conclusion: In low-risk NMBC, the prophylactic effect against postoperative single intravesical instillation with THP was not superior to that with MMC.

Keywords: Single intravesical instillation; low-risk bladder cancer; mitomycin C; pirarubicin.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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28
Anticancer Res




. 2020 Sep;40(9):5319-5325. doi: 10.21873/anticanres.14539.
Clinical Outcome of Surgically Treated Leiomyosarcoma of the Extremities: A Retrospective Overview
Annelies VAN Beeck 1, Michiel VAN DE Sande 2, Veroniek VAN Praag 2, Dietmar Dammerer 3, Jozef Michielsen 4, Thomas Schubert 5, Bilal Kapanci 6, Felix Shumelinsky 6, Johan Somville 4, Sander Dijkstra 2
Affiliations expand
PMID: 32878824
DOI: 10.21873/anticanres.14539

Abstract


Aim: This study was interested in extremity leiomyosarcoma with focus on clinical outcome after surgery with or without adjuvant therapy.

Patients and methods: A retrospective case series of all patients with leiomyosarcoma, surgically treated between 2000 and 2015 and a minimum follow-up of 2 years, was drawn from institutional databases in Belgium and the Netherlands. Postoperative complications were reported with the Radiation Therapy Oncology Group (RTOG) and the Henderson classification.

Results: Seventy-five patients were operated on, of whom 47 underwent (neo)adjuvant therapy. Infection was observed in 11 patients, seven associated with (neo)adjuvant radiotherapy. Dermatological complaints were observed in 26 patients, 10 associated with (neo)adjuvant radiotherapy. Overall survival was 60%. Local recurrence occurred in 11 (15%) patients.

Conclusion: This study describes favourable clinical outcome following (neo)adjuvant radiotherapy. In the future, larger databases on leiomyosarcoma should enhance the power of these findings and define the benefits of adjuvant therapy in leiomyosarcoma.

Keywords: Leiomyosarcoma; clinical outcome; extremity; oncologic; sarcoma; soft-tissue sarcoma; surgical.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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29
Anticancer Res




. 2020 Sep;40(9):5181-5189. doi: 10.21873/anticanres.14521.
Advanced Non-linear Mathematical Model for the Prediction of the Activity of a Putative Anticancer Agent in Human-to-mouse Cancer Xenografts
Sotirios G Liliopoulos 1, George S Stavrakakis 1, Konstantinos S Dimas 2
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PMID: 32878806
DOI: 10.21873/anticanres.14521

Abstract


Background/aim: Mathematical models have long been considered as important tools in cancer biology and therapy. Herein, we present an advanced non-linear mathematical model that can predict accurately the effect of an anticancer agent on the growth of a solid tumor.

Materials and methods: Advanced non-linear mathematical optimization techniques and human-to-mouse experimental data were used to develop a tumor growth inhibition (TGI) estimation model.

Results: Using this mathematical model, we could accurately predict the tumor mass in a human-to-mouse pancreatic ductal adenocarcinoma (PDAC) xenograft under gemcitabine treatment up to five time periods (points) ahead of the last treatment.

Conclusion: The ability of the identified TGI dynamic model to perform satisfactory short-term predictions of the tumor growth for up to five time periods ahead was investigated, evaluated and validated for the first time. Such a prediction model could not only assist the pre-clinical testing of putative anticancer agents, but also the early modification of a chemotherapy schedule towards increased efficacy.

Keywords: Pharmacokinetic (PK)–Pharmacodynamic (PD); TGI model parameters estimation; adaptive tumor growth short-term prediction; deep learning neural networks (DLNN); nonlinear optimization; pancreatic ductal adenocarcinoma (PDAC) xenograft; tumor growth inhibition (TGI) mathematical model; xenografted mice (PDX).

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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30
Anticancer Res




. 2020 Sep;40(9):5201-5210. doi: 10.21873/anticanres.14523.
Total Flavonoids Isolated from Diospyros kaki L. f. Leaves Induced Apoptosis and Oxidative Stress in Human Cancer Cells
L I Chen 1 2, Yuhang Guo 1 3, Gheda Alsaif 4, Ying Gao 5
Affiliations expand
PMID: 32878808
DOI: 10.21873/anticanres.14523

Abstract


Background/aim: Persimmon (Diospyros kaki L.) leaves are popular as a tea infusion in Asia and their main active ingredients are flavonoids. The present study aimed to explore the anticancer properties of flavonoids isolated from persimmon leaves (PLF).

Materials and methods: We investigated the in vitro anti-proliferative activity of PLF against several human cancer cell lines. Apoptosis and intracellular reactive oxygen species (ROS) induced by PLF were accessed using high-content analysis with florescent staining. The ability of PLF to scavenge free radicals was evaluated by 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay.

Results: PLF demonstrated significant inhibition of proliferation of liver, breast, and colorectal cancer cells in vitro. PLF induced apoptosis and increased intracellular ROS levels in HCT116 (colorectal cancer) and HepG2 (liver cancer) cells. In addition, PLF showed strong free radical scavenging ability.

Conclusion: The anti-proliferation activity of PLF against cancer cells was related to the induction of apoptosis and oxidative stress.

Keywords: Persimmon leaf flavonoids; anticancer; antioxidant; apoptosis; reactive oxygen species.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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31
Anticancer Res




. 2020 Sep;40(9):4885-4894. doi: 10.21873/anticanres.14491.
Antitumor Effects and Tumor-specificity of Guaiazulene-3-Carboxylate Derivatives Against Oral Squamous Cell Carcinoma In Vitro
Michito Teratani 1, Shouta Nakamura 1, Hiroshi Sakagami 2, Masakazu Fujise 1, Masashi Hashimoto 1, Noriyuki Okudaira 3, Kenjiro Bandow 4, Yosuke Iijima 5, Junko Nagai 6, Yoshihiro Uesawa 6, Hidetsugu Wakabayashi 7
Affiliations expand
PMID: 32878776
DOI: 10.21873/anticanres.14491

Abstract


Aim: The aim of this study was to investigate the antitumor potential of guaiazulene-3-carboxylate derivatives against oral malignant cells.

Materials and methods: Twelve guaiazulene-3-carboxylate derivatives were synthesized by introduction of either with alkyl group [1-5], alkoxy group [6, 7], hydroxyl group [8, 9] or primary amine [10-12] at the end of sidechains. Tumor-specificity (TS) was calculated by the ratio of mean 50% cytotoxic concentration (CC50) against 3 human oral mesenchymal cell lines to that against 4 human oral squamous cell carcinoma (OSCC) cell lines. Potency-selectivity expression (PSE) was calculated by dividing TS value by CC50value against OSCC cell lines. Cell cycle analysis was performed by cell sorter.

Results: [6, 7] showed the highest TS and PSE values, and induced the accumulation of both subG1 and G2/M cell populations in HSC-2 OSCC cells. Quantitative structure-activity relationship analysis demonstrated that their tumor-specificity was correlated with chemical descriptors that explain the 3D shape, electric state and ionization potential.

Conclusion: Alkoxyl guaiazulene-3-carboxylates [6, 7] can be potential candidates of lead compound for developing novel anticancer drugs.

Keywords: OSCC; QSAR; guaiazulene-3-carboxylate; ionization potential; molecular shape; tumor-specificity.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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32
Anticancer Res




. 2020 Sep;40(9):4907-4912. doi: 10.21873/anticanres.14493.
Luteolin Induces Cytotoxicity in Mix Cellularity Classical Hodgkin's Lymphoma via Caspase Activated-cell Death
Rajendra Gharbaran 1 2, Enyuan Shang 3, Onyekwere Onwumere 2 4, Naomi Codrington 2, Evangelina Dankwa Sarpong 3 2, Stephen Redenti 2 4
Affiliations expand
PMID: 32878778
DOI: 10.21873/anticanres.14493

Abstract


Background/aim: We investigated the effects of luteolin (LUT) on classical Hodgkin's lymphoma (cHL), since such studies in malignant lymphomas are lacking.

Materials and methods: Effect of LUT on cell growth was assessed with water-soluble tetrazolium 1 (WST-1) cell proliferation assay and automated hemocytometry on trypan blue-exclusion assay. Cell death was investigated with acridine orange/ethidium bromide live-dead assay, propidium iodide (PI) flow cytometry, and Annexin-V-PI microscopy. Caspase activation was studied using CellEvent Caspase-3/7 Green detection reagent. High resolution immunofluorescence microscopy was used to detect cleaved-PARP-1.

Results: LUT induced a dose-dependent decrease in the growth of KMH2 and L428 cells, cellular models of mix-cellularity (MC) and nodular sclerosis (NS) cHL, respectively. However, LUT induced cell death only in KMH2, at a higher concentration, and this was associated with caspase activation and cleaved PARP-1.

Conclusion: LUT induces cytotoxicity in the MC-cHL cellular model KMH2 via caspase activation.

Keywords: Hodgkin's lymphoma; Luteolin; cancer; mix cellularity classical Hodgkin's lymphoma.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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33
Anticancer Res




. 2020 Sep;40(9):5277-5283. doi: 10.21873/anticanres.14532.
Salvage Chemotherapy After Nivolumab for Recurrent or Metastatic Head and Neck Carcinoma
Chihiro Fushimi 1, Isaku Okamoto 2, Takashi Matsuki 3, Tatsuo Masubuchi 4, Takuro Okada 2, Hiroki Sato 2, Kiyoaki Tsukahara 2, Takahito Kondo 5, Taku Yamashita 3, Kenji Hanyu 4 2, G O Omura 6, Hideaki Takahashi 7, Yuichiro Tada 4, Kouki Miura 4
Affiliations expand
PMID: 32878817
DOI: 10.21873/anticanres.14532

Abstract


Background/aim: The treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) has remained challenging. The effect of salvage chemotherapy (SCT) after nivolumab has been identified recently in other cancer types. The aim of this study was to examine the efficacy of SCT after nivolumab treatment in patients with R/M HNSCC.

Patients and methods: A retrospective study was conducted at four institutions in Japan. Fifty-six patients were enrolled in the study.

Results: The overall survival (OS) in SCT patients was significantly longer than that in best supportive care (BSC) patients. In the SCT patients, the median OS, median progression-free survival (PFS) and objective response rate (ORR) were 7.3 months, 2.3 months and 36%, respectively. Prognostic factor for OS and ORR was performance score (PS) and previous radiation, respectively.

Conclusion: SCT after nivolumab is associated with better clinical outcomes in patients with R/M HNSCC compared to those receiving BSC.

Keywords: Immune checkpoint inhibitor; Salvage chemotherapy; best supportive care; head and neck carcinoma; nivolumab; recurrent or metastatic.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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34
Anticancer Res




. 2020 Sep;40(9):5313-5317. doi: 10.21873/anticanres.14538.
Second-line Dasatinib Therapy Improved Compliance and Deep Molecular Responses in Imatinib-intolerant Chronic Myeloid Leukemia Patients
Uros Markovic 1, Anna Bulla 1, Salvatore Leotta 1, Stefania Stella 2, Maria Letizia Consoli 1, Loredana TambÈ 1, Concetta Conticello 1, Francesco DI Raimondo 1, Fabio Stagno 3
Affiliations expand
PMID: 32878823
DOI: 10.21873/anticanres.14538

Abstract


Background/aim: Imatinib (IM) is the standard-of-care treatment for most chronic myeloid leukemia (CML) patients in chronic phase (CP). However, some patients suffer from low-grade side-effects that, in the long run, severely affect the quality of life and require treatment discontinuation due to toxicities. Fortunately, there are several therapeutic alternatives for these patients. Among them, the second-generation tyrosine kinase inhibitor dasatinib (DAS), used as second-line treatment, has shown to be a valid option in patients with CP-CML after intolerance to prior IM.

Patients and methods: Herein, we report on seven CP-CML patients who achieved a stable major molecular response (MMR) with IM-therapy, but were shifted to DAS treatment due to recurrent low-grade IM-intolerances (grades 1-2).

Results and conclusion: All patients received conventional DAS treatment with a median daily dose of 83.3 mg. Treatment was well tolerated and side-effects were mild. In addition, after a median follow-up of 25 months (range=24-43 months) a deep molecular response (DMR) (either MR4 or MR4.5) was achieved in all patients after 24 months of treatment. This finding, although limited to a small cohort of CP-CML patients, supports the view that a therapy switch from IM to DAS induces a reduction of symptom burden, improves patient compliance and shows clinical efficacy in achieving and sustaining deep molecular responses.

Keywords: BCR-ABL1; Imatinib; TKI; chronic myeloid leukemia; dasatinib; second-line treatment.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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35
Anticancer Res




. 2020 Sep;40(9):5229-5235. doi: 10.21873/anticanres.14526.
Phase I Study of LFA102 in Patients With Advanced Breast Cancer or Castration-resistant Prostate Cancer
Hironobu Minami 1, Yuichi Ando 2, Kenji Tamura 3, Takeshi Tajima 4, Randi Isaacs 5
Affiliations expand
PMID: 32878811
DOI: 10.21873/anticanres.14526

Abstract


Background/aim: The prolactin receptor (PRLR) is implicated in the tumorigenesis of breast and prostate cancers where it drives cell proliferation, survival, and migration. LFA102 is a humanized monoclonal antibody against PRLR with promising preclinical antitumor activity. To determine the maximum tolerated dose or a recommended dose, and to delineate the pharmacokinetic profile of LFA102 in Japanese patients, we conducted a phase I study.

Patients and methods: LFA102 was intravenously infused every 4 weeks to patients with advanced breast or castration-resistant prostate cancer, and the dose increased from 3 to 40 mg/kg.

Results: Fourteen patients were treated, and toxicities were reported in 9 (64%) patients. They were all grade 1 or 2, and the most frequently observed toxicity was nausea (3 patients, 21%). No dose-limiting toxicities were observed. LFA102 did not show antitumor activity as a single agent.

Conclusion: Treatment with LFA102 was well tolerated.

Keywords: Prolactin receptor; breast cancer; prostate cancer.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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36
Review
Anticancer Res




. 2020 Sep;40(9):4819-4828. doi: 10.21873/anticanres.14485.
Neoadjuvant Chemotherapy in Locally Advanced Cervical Cancer: Review of the Literature and Perspectives of Clinical Research
Angiolo Gadducci 1, Stefania Cosio 2
Affiliations expand
PMID: 32878770
DOI: 10.21873/anticanres.14485

Abstract


Concurrent cisplatin-based chemotherapy and radiotherapy (CCRT) plus brachytherapy is standard treatment for locally advanced cervical cancer. Platinum-based neoadjuvant chemotherapy (NACT) followed by radical hysterectomy has been proposed as an alternative approach, especially for patients with stage Ib2-IIb disease. This review analyzes the most commonly used combination regimens in this clinical setting and the randomized trials comparing chemo-surgery versus definitive radiotherapy or CCRT. The combination of paclitaxel plus ifosfamide plus cisplatin (TIP regimen) obtained the highest rates of optimal pathological response, associated with elevated hematological toxicity. In a recent phase II study, a dose-dense regimen consisting of weekly paclitaxel plus carboplatin for 9 cycles has achieved optimal pathological response rates similar to those of TIP with better toxicity profile. Further studies are strongly warranted to better define the optimal regimen for the patients selected to receive NACT followed by radical surgery.

Keywords: Cervical cancer; concurrent chemoradiation; neoadjuvant chemotherapy; radical surgery; radiotherapy; review.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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37
Anticancer Res




. 2020 Sep;40(9):5211-5219. doi: 10.21873/anticanres.14524.
Anti-tumor Activity of the Small Molecule Inhibitor PRI-724 Against β-Catenin-activated Hepatocellular Carcinoma
Ryosuke Gabata 1 2, Kenichi Harada 3, Yuki Mizutani 2, Hirofumi Ouchi 2, Kaori Yoshimura 2, Yasunori Sato 2, Azusa Kitao 4, Kiminori Kimura 5, Hiroyuki Kouji 6 7, Tomoharu Miyashita 1, Hidehiro Tajima 1, Tetsuo Ohta 1
Affiliations expand
PMID: 32878809
DOI: 10.21873/anticanres.14524

Abstract


Background/aim: CBP is a transcriptional coactivator in the Wnt/β-catenin pathway that is related to cell kinetics and differentiation. This study aimed to characterize β-catenin-activated hepatocellular carcinoma (HCC) and evaluate the direct effects of PRI-724 (a selective inhibitor of Wnt/β-catenin/CBP signaling) on HCC.

Materials and methods: Immunohistochemistry for β-catenin was performed in 199 HCC resected samples. Moreover, using cultured HCC cell lines, cell kinetics and its related proteins were analyzed after treatment of cells with C-82 (active form of PRI-724).

Results: Nuclear β-catenin expression was found in 18% of HCC cases and the tumor sizes in these positive samples were larger. In HCC cell lines with a constitutively activated β-catenin, C-82 inhibited cell proliferation. C-82 led to an increase in the percentage of cells in the G0/G1 phase of the cell cycle. The percentage of cells in the sub-G1 phase also increased. Moreover, C-82 treatment significantly decreased the expression of cell proliferating markers and increased the expression of apoptosis-related proteins.

Conclusion: PRI-724(C-82) may be a novel drug for β-catenin-activated HCC therapy.

Keywords: CBP; Hepatocellular carcinoma; PRI-724; Wnt; inhibitor; β-catenin.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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38
Anticancer Res




. 2020 Sep;40(9):5171-5180. doi: 10.21873/anticanres.14520.
Inhibitory Effects of Beraprost Sodium in Murine Hepatic Sinusoidal Obstruction Syndrome
Makoto Nakura 1, Tomoharu Miyashita 2, Yasuhiko Yamamoto 3, Satoshi Takada 1, Shunsuke Kanou 1, Hidehiro Tajima 1, Hiroyuki Takamura 4, Tetsuo Ohta 1
Affiliations expand
PMID: 32878805
DOI: 10.21873/anticanres.14520

Abstract


Background/aim: In this study, the liver sinusoidal endothelial cells (LSECs)-protective effects of beraprost sodium (BPS) were investigated using mice with monocrotaline (MCT)-induced sinusoidal obstruction syndrome (SOS).

Materials and methods: The mice were divided into BPS, placebo and control groups. They were killed 48 h after MCT administration, and blood samples and liver tissues were evaluated. Immunostaining was performed using anti-SE-1 and anti-CD42b antibodies, whereas plasminogen activator inhibitor (PAI-1) and endothelial nitric oxide synthase (eNOS) levels were evaluated using western blot or real-time RT-PCR.

Results: On pathological examination, SOS-related findings were observed in zone 3 in the placebo group; however, these were significantly suppressed in the BPS group. SE-1 staining showed a consistent number of LSECs in the BPS group compared with that in the placebo group, while CD42b staining showed a significant decrease in the number of extravasated platelet aggregation (EPA) in the BPS group. PAI-1 expression was significantly lower in the BPS group than in the placebo group; however, eNOS expression was significantly higher in the BPS group than in the placebo group.

Conclusion: Prophylactic administration of BPS is useful for suppressing the development of SOS through the protective effects of LSEC.

Keywords: Beraprost sodium; liver sinusoidal endothelial cells; liver transplantation; oxaliplatin based chemotherapy; sinusoidal obstruction syndrome; veno-occlusive disease.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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39
Anticancer Res




. 2020 Sep;40(9):5221-5227. doi: 10.21873/anticanres.14525.
Gamma/Delta T-Cells Enhance Carboplatin-induced Cytotoxicity Towards Advanced Bladder Cancer Cells
Yueh Pan 1, Ya-Hsu Chiu 2, Shao-Chih Chiu 2 3, DER-Yang Cho 2 4 5, Liang-Ming Lee 1 6, Yu-Ching Wen 1 6, Jacqueline Whang-Peng 7 8, Chi-Hao Hsiao 9 6, Ping-Hsiao Shih 10
Affiliations expand
PMID: 32878810
DOI: 10.21873/anticanres.14525

Abstract


Background/aim: Bladder cancer (BLCA, urothelial bladder cancer) is one of the most common malignancies with increasing incidence and mortality worldwide. Poor diagnosis and the limitation of treatment is still an unmet need in clinical practice. γδ T-Cells have been paid increasing attention because of their potent cytotoxicity against tumors. Herein, we investigated the cytolytic effect of γδ T-cells in combination with the chemotherapeutic drug, carboplatin, against BLCA cells.

Materials and methods: The standard protocol for the induction and expansion of peripheral blood mononuclear cell-derived γδ T-cells was a zoledronic acid/interleukin-2-based medium system for 2 weeks. The cytotoxicity of γδ T-cells with and without carboplatin against BLCA cells was examined.

Results: After incubation, T-cell receptor-positive γδ T-cells showed a natural killer cell-like phenotypic characteristic and dose-dependently increased cytotoxicity against BLCA cells. Interestingly, we found that in advanced BLCA cells, which were more resistant to carboplatin, the cell viability was significantly (p<0.05) reduced in the presence of γδ T-cells.

Conclusion: Our findings showed that γδ T-cell therapy has potent benefit in cancer treatment.

Keywords: Immunocellular therapy; bladder cancer; chemotherapy; cytotoxicity; gamma/delta T-cell.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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40
Anticancer Res




. 2020 Sep;40(9):5255-5261. doi: 10.21873/anticanres.14529.
Cabazitaxel - A Treatment Option in Recurrent Platinum-resistant Ovarian Cancer
Christine Vestergaard Madsen 1, Parvin Adimi 2, Anders Jakobsen 2 3, Karina Dahl Steffensen 2 3
Affiliations expand
PMID: 32878814
DOI: 10.21873/anticanres.14529

Abstract


Background/aim: Treatment of recurrent platinum-resistant ovarian cancer remains challenging due to the development of resistance to chemotherapy. Cabazitaxel is a new taxane that has demonstrated beneficial effect in prostate cancer patients resistant to docetaxel. Therefore, it could be anticipated to possibly also have an effect on chemotherapy resistant ovarian cancer.

Patients and methods: Twenty-six patients with chemotherapy-resistant epithelial ovarian cancer, fallopian tube or peritoneal cancer were treated with cabazitaxel at a dose of 25 mg/m2 (on day 1 of each 3-week cycle), until progression or inacceptable toxicity, between September 2015 and April 2018. The fraction of patients without progression after three months of treatment was the primary endpoint. Prophylaxis with granulocyte colony-stimulating factor (G-CSF) was prescribed to all patients.

Results: The median number of cabazitaxel infusions was 4 (range=1-18). In general, cabazitaxel was well-tolerated. The fraction of patients alive and without progression after 3 months of treatment was 54% (14/26). The response rate was 46% (12/26) according to the Gynecological Cancer Intergroup (GCIG) criteria for CA125. Partial response (PR), evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST), was found in 4/26 patients (15%). By intention-to-treat analysis, the median progression-free survival (PFS) was 3.9 months (95% CI=1.9-4.4) using the combination of CA125 or RECIST (whichever came first), while the median overall survival (OS) was 8.4 months (95% CI=5.1-11.0).

Conclusion: Cabazitaxel holds promise as a drug in recurrent platinum-resistant ovarian cancer. It demonstrated efficacy and in general, the toxicity was manageable.

Keywords: Platinum-resistance; cabazitaxel; chemotherapy; phase II randomized study; recurrent ovarian cancer.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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41
Anticancer Res




. 2020 Sep;40(9):5285-5290. doi: 10.21873/anticanres.14533.
Continuous Administration of Bevacizumab After Disease Progression in Recurrent Ovarian Cancer: A Retrospective Observational Study
Terumi Tanigawa 1, Maki Matoda 2, Makiko Omi 2, Yoichi Aoki 2, Sachiho Netsu 2, Hidetaka Nomura 2, Sanshiro Okamoto 2, Kohei Omatsu 2, Mayu Yunokawa 2, Hiroyuki Kanao 2, Nobuhiro Takeshima 2
Affiliations expand
PMID: 32878818
DOI: 10.21873/anticanres.14533

Abstract


Background/aim: Chemotherapy with additional bevacizumab is the standard treatment for primary and recurrent ovarian cancer. We aimed to investigate the clinical utility and safety of bevacizumab when used in combination with chemotherapy after disease progression.

Patients and methods: This retrospective, observational study recruited patients treated for recurrent ovarian cancer from 2014 to 2016. We evaluated the effects of bevacizumab with chemotherapy in patients whose disease had progressed following treatment with bevacizumab. We assessed progression-free survival and adverse events.

Results: Thirty-three patients received post-progression treatment with bevacizumab. The median progression-free survival was 8.7 months (95% confidence interval=5.5-11). The progression-free survival was compared pre- and post-progression treatment, and was longer in platinum-resistant than platinum-sensitive cases after treatment (p=0.06). The most common non-hematological toxicity was proteinuria. The incidence of serious adverse events was low.

Conclusion: Continuous administration of bevacizumab may be beneficial for ovarian cancer patients after disease progression.

Keywords: Bevacizumab; continuous administration; disease progression; progression-free survival; recurrent ovarian cancer.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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42
Anticancer Res




. 2020 Sep;40(9):5043-5048. doi: 10.21873/anticanres.14507.
Inhibitory Effect of Eicosapentaenoic Acid on the Migration of the Esophageal Squamous Cell Carcinoma Cell Line TE-1
Hisako Kubota 1, Toshihiro Hirai 2, Akira Yamauchi 3, Ayako Ogo 4, Hideo Matsumoto 2, Tomio Ueno 5
Affiliations expand
PMID: 32878792
DOI: 10.21873/anticanres.14507

Abstract


Background/aim: Eicosapentaenoic acid (EPA) inhibits NF-ĸB activation and IL-6 production in TE-1 esophageal cancer cells. NF-ĸB is related to cancer cell migration. The aim of this study is to evaluate whether EPA has a metastasis suppressing effect. Herein, we investigated EPA-treated TE-1 cell migration using TAXIScan.

Materials and methods: EZ-TAXIScan® was used to verify whether EPA inhibits cancer cell chemotaxis.

Results: Using 50% fetal bovine serum (chemoattractant) without EPA (positive control), average velocity was 0.306±0.084 μm/min compared to 0.162±0.067 μm/min without chemoattraction (negative control). Directionalities of positive and negative controls were 1.039±0.152 and 0.488±0.251 radians, respectively, indicating a significant increase in migration of the positive control compared to that of the negative control. Average velocities were 0.306±0.084 (no EPA), 0.288±0.078 (100 μM EPA), and 0.240±0.054 200 μM (EPA) μm/min, indicating that EPA reduced velocity dose-dependently. Average directionalities were 1.039±0.152 (no EPA), 0.967±0.164 (100 μM EPA), and 0.901±0.146 (200 μM EPA) radians, indicating that EPA also inhibited directionality dose-dependently.

Conclusion: EPA suppresses directional migration of TE-1 cells.

Keywords: Chemotaxis; TE1-cells; eicosatetraenoic acids; squamous cell carcinoma.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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43
Anticancer Res




. 2020 Sep;40(9):5035-5041. doi: 10.21873/anticanres.14506.
Up-regulation of Death Receptor 5/TRAIL-R2 Mediates Apoptosis Induced by N,N'-[(3,4-dimethoxyphenyl)methylene] Biscinnamide in Cancer Cells
Ii Hiromi 1, Susumu Nakata 2, Jun'ichi Uenishi 3 4
Affiliations expand
PMID: 32878791
DOI: 10.21873/anticanres.14506

Abstract


Background/aim: Based on the cytotoxic agent (-)-zampanolide, N,N'-(arylmethylene)bisamides were designed and synthesized as candidate anti-cancer agents. Among them, N,N'-[(3,4-dimethoxyphenyl)methylene]biscinnamide (DPMBC) was identified as the most potent cytotoxic analog against cancer cells. In this study, we investigated the mechanisms underlying DPMBC-induced cell death in HL-60 human promyelocytic leukemia and PC-3 human prostate cancer cells.

Materials and methods: Cell growth was assessed by the WST-8 assay. Induction of apoptosis was assessed by nuclear morphology, DNA ladder formation, and flow cytometry using Annexin V staining. Activation of factors in the apoptotic signaling pathway was assessed by western blot analyses. Knockdown of death receptor 5 (DR5) was performed using siRNA.

Results: DPMBC up-regulated expression levels of DR5 protein and induced apoptosis through the extrinsic apoptotic pathway mediated by DR5 and caspases.

Conclusion: DPMBC is an extrinsic apoptosis inducer, which has potential as a therapeutic agent for cancer therapy.

Keywords: N,N’-(arylmethylene)biscinnamide; apoptosis; cancer cells; caspase; death receptor 5.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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44
Anticancer Res




. 2020 Sep;40(9):5097-5106. doi: 10.21873/anticanres.14513.
Assessing the Anti-cancer Therapeutic Mechanism of a Herbal Combination for Breast Cancer on System-level by a Network Pharmacological Approach
Ho-Sung Lee 1, Dal-Seok Oh 2
Affiliations expand
PMID: 32878798
DOI: 10.21873/anticanres.14513

Abstract


Background/aim: Accumulating evidence has shown therapeutic effects of herbals on breast cancer, a commonly diagnosed malignancy in women worldwide. However, their underlying mechanisms remain unclear. We aimed to explore the mode of action of a recently developed herbal combination at system-level.

Materials and methods: We employed network pharmacological approaches to study the mechanism of a combination of three herbals, Astragalus membranaceus, Angelica gigas and Trichosanthes kirilowii by investigating active compounds and performing functional enrichment analysis for the interacting targets.

Results: For in silico pharmacokinetic evaluation, ten active ingredients interacted with fifty-six breast cancer-associated therapeutic targets. Functional enrichment analysis revealed that TNF, estrogen, PI3K-Akt and MAPK signaling pathways were involved in tumorigenesis and development of breast cancer. The pharmacological mechanisms might be associated with cellular effects on proliferation, cell cycle process and apoptosis.

Conclusion: The present study provides novel insights into the system-level pharmacological mechanisms underlying a herbal combination used for breast cancer therapies.

Keywords: Systems biology; breast cancer; combination; herbal; network pharmacology; pharmacological mechanism.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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45
Anticancer Res




. 2020 Sep;40(9):5091-5095. doi: 10.21873/anticanres.14512.
YM155 Reverses Cabazitaxel Resistance in Castration-resistant Prostate Cancer by Reducing Survivin Expression
Takeshi Miyao 1, Hidekazu Koike 2, Yoshitaka Sekine 1, Akira Ohtsu 1, Daisuke Oka 1, Kazuhiro Suzuki 1
Affiliations expand
PMID: 32878797
DOI: 10.21873/anticanres.14512

Abstract


Background/aim: The purpose of the present study was to clarify whether treatment with YM155, a novel small-molecule inhibitor of survivin, reversed cabazitaxel resistance in castration-resistant prostate cancer (CRPC).

Materials and methods: Cabazitaxel resistance was induced in the castration-resistant prostate cancer cell line, 22Rv1-CR. In vitro and in vivo models were used to test the efficacy of YM155 and cabazitaxel.

Results: Survivin gene expression was significantly higher in 22Rv1-CR than its parent cells (22Rv1). In 22Rv1-CR cells, YM155 significantly reduced expression of the survivin gene in a concentration-dependent manner. YM155 alone was poorly effective; however, it significantly enhanced the anticancer effects of cabazitaxel on 22Rv1-CR in vitro and in vivo.

Conclusion: Inhibition of survivin by YM155 overcomes cabazitaxel resistance in CRPC cells.

Keywords: Castration-resistant prostate cancer; YM155; cabazitaxel; drug therapy; inhibitor of apoptosis proteins; survivin.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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46
Anticancer Res




. 2020 Sep;40(9):5237-5243. doi: 10.21873/anticanres.14527.
Mogamulizumab Plus EPOCH Therapy for Patients With Newly Diagnosed Aggressive Adult T-cell Leukemia/lymphoma
Tatsuro Jo 1, Kaori Matsuzaka 2, Haruna Shioya 2, Hiroo Tominaga 2, Takahiro Sakai 2, Yohei Kaneko 2, Shizuka Hayashi 2, Masatoshi Matsuo 3, Jun Taguchi 3, Kuniko Abe 4, Kazuto Shigematsu 4, Ritsuko Kubota-Koketsu 5
Affiliations expand
PMID: 32878812
DOI: 10.21873/anticanres.14527

Abstract


Background/aim: Adult T-cell leukemia/lymphoma (ATLL) is a relatively refractory CD4-positive peripheral T-cell lymphoma. VCAP-AMP-VECP (mLSG15) is one of the standard chemotherapeutic regimens for patients with aggressive ATLL. Mogamulizumab (moga), a monoclonal antibody for C-C chemokine receptor 4 antigen expressed on the cell surface, has recently been poised for use as monotherapy and in combination with chemotherapy. However, to date, a significant survival benefit has not been obtained with the combination of moga + mLSG15 therapy.

Patients and methods: We retrospectively analyzed 77 patients diagnosed with aggressive ATLL. Of them, 22 were treated with moga + a chemotherapy regimen comprised of etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisolone (EPOCH), 16 with moga + mLSG15, and 39 with chemotherapy alone.

Results: A risk reduction of approximately 30% was obtained with moga + EPOCH compared with moga + mLSG15.

Conclusion: The addition of moga to chemotherapy did not result in a survival benefit compared with chemotherapy alone. However, a statistically significant overall survival benefit was observed in patients with moga-induced skin disorders.

Keywords: Adult T-cell leukemia/lymphoma; EPOCH; mogamulizumab.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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47
Anticancer Res




. 2020 Sep;40(9):4921-4928. doi: 10.21873/anticanres.14495.
Phenothiazines and Selenocompounds: A Potential Novel Combination Therapy of Multidrug Resistant Cancer
MÁriÓ GajdÁcs 1 2, MÁrta NovÉ 1, Ákos Csonka 1 3, Borisz Varga 1 4, Carmen SanmartÍn 5 6, Enrique DomÍnguez-Álvarez 7, Gabriella Spengler 8
Affiliations expand
PMID: 32878780
DOI: 10.21873/anticanres.14495

Abstract


Background/aim: Phenothiazines constitute a versatile family of compounds in terms of biological activity, which have also gained a considerable attention in cancer research.

Materials and methods: Three phenothiazines (promethazine, chlorpromazine and thioridazine) have been tested in combination with 11 active selenocompounds against MDR (ABCB1-overexpressing) mouse T-lymphoma cells to investigate their activity as combination chemotherapy and as antitumor adjuvants in vitro with a checkerboard combination assay.

Results: Seven selenocompounds showed toxicity on mouse embryonic fibroblasts, while three showed selectivity towards tumor cells. Two compounds showed synergism with all tested phenothiazines in low concentration ranges (1.46-11.25 μM). Thioridazine was the most potent among the three phenothiazines.

Conclusion: Phenothiazines belonging to different generations showed different levels of adjuvant activities. All the tested phenothiazines are already approved medicines with known pharmacological and toxicity profiles, therefore, their use as adjuvants in cancer may be considered as a potential drug repurposing strategy.

Keywords: Cancer; T-lymphoma; combination chemotherapy; multidrug resistance; phenothiazines; selenoanhydride; selenoesters.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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48
Anticancer Res




. 2020 Sep;40(9):5115-5124. doi: 10.21873/anticanres.14515.
Antitumor Effect of Shikonin, a PKM2 Inhibitor, in Cholangiocarcinoma Cell Lines
Unchalee Thonsri 1 2, Wunchana Seubwai 3 4, Sakda Waraasawapati 5, Sopit Wongkham 1 2, Thidarat Boonmars 2 6, Ubon Cha'on 1 2, Chaisiri Wongkham 1 2
Affiliations expand
PMID: 32878800
DOI: 10.21873/anticanres.14515

Abstract


Background/aim: Pyruvate kinase M2 (PKM2) is an enzyme that is predominantly overexpressed in various types of cancer. The role of PKM2 in liver fluke-associated cholangiocarcinoma (CCA) remains unclear. This study aimed to investigate the antitumor activity of shikonin, a PKM2 inhibitor, in CCA cells.

Materials and methods: Immunohistochemistry and immunoblotting were used to determine PKM2 expression in CCA tissues and cells. Antiproliferative effects of shikonin were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, colony-formation and trypan blue exclusion assays. The anti-metastatic activity of shikonin was determined using the Boyden chamber assay. Mechanisms by which shikonin inhibited CCA progression were determined.

Results: PKM2 was overexpressed in CCA compared to normal bile duct epithelial cells. Shikonin significantly inhibited growth, and migration of CCA cells while inducing their death. A mechanistic study revealed that antitumor effects of shikonin in CCA cells depended on increased production of reactive oxygen species.

Conclusion: Shikonin may be a novel therapeutic agent for patients with CCA.

Keywords: Cholangiocarcinoma; pyruvate kinase M2; reactive oxygen species; shikonin.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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49
Anticancer Res




. 2020 Sep;40(9):5245-5254. doi: 10.21873/anticanres.14528.
Higher BMI, But Not Sarcopenia, Is Associated With Pembrolizumab-related Toxicity in Patients With Advanced Melanoma
Janice B Hu 1, Surya Ravichandran 1, Christel Rushing 2 3, Georgia M Beasley 4, Brent A Hanks 5, Sin-Ho Jung 2 3, April K S Salama 5, Lisa Ho 6, Paul J Mosca 7
Affiliations expand
PMID: 32878813
DOI: 10.21873/anticanres.14528

Abstract


Background/aim: To determine whether BMI and sarcopenia were related to treatment-limiting toxicity or efficacy of pembrolizumab treatment in melanoma patients.

Patients and methods: Medical records for melanoma patients undergoing pembrolizumab treatment at Duke University from January 2014 to September 2018 were reviewed. Pre-treatment measurements such as BMI were collected. Pre-treatment CT imaging was used to determine psoas muscle index (PMI). Patients in the lowest sex-specific tertile of PMI were sarcopenic. Logistic regression measured associations with treatment toxicity and response. Kaplan-Meier analysis assessed progression-free survival (PFS) and overall survival (OS).

Results: Among 156 patients, the overall objective response rate was 46.2% and 29 patients (18.6%) experienced treatment-limiting toxicity. Sarcopenia was not significantly associated with toxicity, response, or survival. However, obese patients (BMI >30) experienced higher rates of toxicity (p=0.0007).

Conclusion: Sarcopenia did not appear to predict clinically relevant outcomes. Obesity, however, represents a readily available predictor of pembrolizumab toxicity.

Keywords: Melanoma; adverse reactions; body mass index; clinical decision-making; drug-related side effects; monoclonal antibodies; pembrolizumab; retrospective studies; sarcopenia.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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Anticancer Res




. 2020 Sep;40(9):4961-4968. doi: 10.21873/anticanres.14499.
Inhibition of Retinoblastoma Cell Growth by CEP1347 Through Activation of the P53 Pathway
Keita Togashi 1 2, Masashi Okada 3, Shuhei Suzuki 1 4, Tomomi Sanomachi 1 4, Shizuka Seino 1, Masahiro Yamamoto 1, Hidetoshi Yamashita 2, Chifumi Kitanaka 3 5
Affiliations expand
PMID: 32878784
DOI: 10.21873/anticanres.14499

Abstract


Background/aim: Despite advances in treatment modalities, the visual prognosis of retinoblastoma still remains unsatisfactory, underscoring the need to develop novel therapeutic approaches.

Materials and methods: The effect on the growth of six human retinoblastoma cell lines and a normal human fibroblast cell line of CEP1347, a small-molecule kinase inhibitor originally developed for the treatment of Parkinson's disease and therefore with a known safety profile in humans, was examined. The role of the P53 pathway in CEP1347-induced growth inhibition was also investigated.

Results: CEP1347 selectively inhibited the growth of retinoblastoma cell lines expressing murine double minute 4 (MDM4), a P53 inhibitor. Furthermore, CEP1347 reduced the expression of MDM4 and activated the P53 pathway in MDM4-expressing retinoblastoma cells, which was required for the inhibition of their growth by CEP1347.

Conclusion: We propose CEP1347 as a promising candidate for the treatment of retinoblastomas, where functional inactivation of P53 as a result of MDM4 activation is reportedly common.

Keywords: CDKN1A; Drug repositioning; MDM2; MDMX; P21WAF1/CIP1; repurposing.

Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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