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Obatoclax and Paclitaxel Synergistically Induce Apoptosis and Overcome Paclitaxel Resistance in Urothelial Cancer Cells

1
Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Seville, Spain
2
Department of Oncology, Hospital Universitario Virgen del Rocío, 41013 Seville, Spain
3
Department of Urology, Hospital Universitario Virgen del Rocío, 41013 Seville, Spain
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Department of Microbiology, Faculty of Biology, Universidad de Sevilla, 41012 Seville, Spain
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Department of Pathology, Hospital Universitario Virgen del Rocío, 41013 Seville, Spain
*
Author to whom correspondence should be addressed.
Cancers 2018, 10(12), 490; https://doi.org/10.3390/cancers10120490
Received: 6 November 2018 / Revised: 28 November 2018 / Accepted: 3 December 2018 / Published: 5 December 2018
Paclitaxel is a treatment option for advanced or metastatic bladder cancer after the failure of first-line cisplatin and gemcitabine, although resistance limits its clinical benefits. Mcl-1 is an anti-apoptotic protein that promotes resistance to paclitaxel in different tumors. Obatoclax, a BH3 mimetic of the Bcl-2 family of proteins, antagonizes Mcl-1 and hence may reverse paclitaxel resistance in Mcl-1-overexpressing tumors. In this study, paclitaxel-sensitive 5637 and -resistant HT1197 bladder cancer cells were treated with paclitaxel, obatoclax, or combinations of both. Apoptosis, cell cycle, and autophagy were measured by Western blot, flow cytometry, and fluorescence microscopy. Moreover, Mcl-1 expression was analyzed by immunohistochemistry in bladder carcinoma tissues. Our results confirmed that paclitaxel alone induced Mcl-1 downregulation and apoptosis in 5637, but not in HT1197 cells; however, combinations of obatoclax and paclitaxel sensitized HT1197 cells to the treatment. In obatoclax-treated 5637 and obatoclax + paclitaxel-treated HT1197 cells, the blockade of the autophagic flux correlated with apoptosis and was associated with caspase-dependent cleavage of beclin-1. Obatoclax alone delayed the cell cycle in 5637, but not in HT1197 cells, whereas combinations of both retarded the cell cycle and reduced mitotic slippage. In conclusion, obatoclax sensitizes HT1197 cells to paclitaxel-induced apoptosis through the blockade of the autophagic flux and effects on the cell cycle. Furthermore, Mcl-1 is overexpressed in many invasive bladder carcinomas, and it is related to tumor progression, so Mcl-1 expression may be of predictive value in bladder cancer. View Full-Text
Keywords: bladder cancer; obatoclax; paclitaxel; autophagy; apoptosis bladder cancer; obatoclax; paclitaxel; autophagy; apoptosis
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Jiménez-Guerrero, R.; Gasca, J.; Flores, M.L.; Pérez-Valderrama, B.; Tejera-Parrado, C.; Medina, R.; Tortolero, M.; Romero, F.; Japón, M.A.; Sáez, C. Obatoclax and Paclitaxel Synergistically Induce Apoptosis and Overcome Paclitaxel Resistance in Urothelial Cancer Cells. Cancers 2018, 10, 490.

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