Obatoclax, a BH3 Mimetic, Enhances Cisplatin-Induced Apoptosis and Decreases the Clonogenicity of Muscle Invasive Bladder Cancer Cells via Mechanisms That Involve the Inhibition of Pro-Survival Molecules as Well as Cell Cycle Regulators

被引:19
|
作者
Steele, Thomas M. [1 ,2 ,3 ]
Talbott, George C. [1 ]
Sam, Anhao [1 ]
Tepper, Clifford G. [4 ]
Ghosh, Paramita M. [2 ,3 ,4 ]
Vinall, Ruth L. [1 ]
机构
[1] Calif Northstate Univ Coll Pharm CNUCOP, Dept Pharmaceut & Biomed Sci, Elk Grove, CA 95757 USA
[2] VA Northern Calif Hlth Care Syst VANCHCS, Sacramento, CA 95655 USA
[3] Univ Calif Davis, Dept Urol Surg, Sch Med, Sacramento, CA 95817 USA
[4] Univ Calif Davis, Sch Med, Dept Biochem & Mol Med, Sacramento, CA 95817 USA
关键词
bladder cancer; BH3; mimetics; Obatoclax; cisplatin; apoptosis; BCL-2 ANTISENSE OLIGONUCLEOTIDE; EXPRESSION; RESISTANCE; AUTOPHAGY; P53; MICRORNA-34A; RADIOTHERAPY; CYSTECTOMY; PATHWAYS; GX15-070;
D O I
10.3390/ijms20061285
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Several studies by our group and others have determined that expression levels of Bcl-2 and/or Bcl-xL, pro-survival molecules which are associated with chemoresistance, are elevated in patients with muscle invasive bladder cancer (MI-BC). The goal of this study was to determine whether combining Obatoclax, a BH3 mimetic which inhibits pro-survival Bcl-2 family members, can improve responses to cisplatin chemotherapy, the standard of care treatment for MI-BC. Three MI-BC cell lines (T24, TCCSuP, 5637) were treated with Obatoclax alone or in combination with cisplatin and/or pre-miR-34a, a molecule which we have previously shown to inhibit MI-BC cell proliferation via decreasing Cdk6 expression. Proliferation, clonogenic, and apoptosis assays confirmed that Obatoclax can decrease cell proliferation and promote apoptosis in a dose-dependent manner. Combination treatment experiments identified Obatoclax + cisplatin as the most effective treatment. Immunoprecipitation and Western analyses indicate that, in addition to being able to inhibit Bcl-2 and Bcl-xL, Obatoclax can also decrease cyclin D1 and Cdk4/6 expression levels. This has not previously been reported. The combined data demonstrate that Obatoclax can inhibit cell proliferation, promote apoptosis, and significantly enhance the effectiveness of cisplatin in MI-BC cells via mechanisms that likely involve the inhibition of both pro-survival molecules and cell cycle regulators.
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页数:15
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