Publication: Obatoclax and Paclitaxel Synergistically Induce Apoptosis and Overcome Paclitaxel Resistance in Urothelial Cancer Cells.
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Identifiers
Date
2018-12-05
Authors
Jimenez-Guerrero, Rocio
Gasca, Jessica
Flores, M Luz
Perez-Valderrama, Begoña
Tejera-Parrado, Cristina
Medina, Rafael
Tortolero, Maria
Romero, Francisco
Japon, Miguel A
Saez, Carmen
Advisors
Journal Title
Journal ISSN
Volume Title
Publisher
MDPI AG
Abstract
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.
Description
MeSH Terms
Gemcitabine
Cisplatin
Beclin-1
Caspases
Apoptosis Regulatory Proteins
Paclitaxel
Urinary Bladder Neoplasms
Autophagy
Blotting, Western
Carcinoma
Cisplatin
Beclin-1
Caspases
Apoptosis Regulatory Proteins
Paclitaxel
Urinary Bladder Neoplasms
Autophagy
Blotting, Western
Carcinoma
DeCS Terms
Paclitaxel
Células
Neoplasias
Carcinoma
Gemcitabina
Inmunohistoquímica
Proteínas
Western Blotting
Autofagia
Cisplatino
Células
Neoplasias
Carcinoma
Gemcitabina
Inmunohistoquímica
Proteínas
Western Blotting
Autofagia
Cisplatino
CIE Terms
Keywords
apoptosis, autophagy, bladder cancer, obatoclax, paclitaxel
Citation
Jiménez-Guerrero R, Gasca J, Flores ML, Pérez-Valderrama B, Tejera-Parrado C, Medina R, et al. Obatoclax and Paclitaxel Synergistically Induce Apoptosis and Overcome Paclitaxel Resistance in Urothelial Cancer Cells. Cancers (Basel). 2018 Dec 5;10(12):490.