Bcl-2 modulation to activate apoptosis in prostate cancer.
Apoptosis resistance is a hallmark of cancer linked to disease progression and treatment resistance, which has led to the development of anticancer therapeutics that restore apoptotic function. Antiapoptotic Bcl-2 is frequently overexpressed in refractory prostate cancer and increased following standard hormonal therapy and chemotherapy; however, the rationally designed Bcl-2 antagonist, ABT-737, has not shown single agent apoptosis-promoting activity against human prostate cancer cell lines. This is likely due to the coordinate expression of antiapoptotic, Bcl-2-related Mcl-1 that is not targeted by ABT-737. We developed a mouse model for prostate cancer in which apoptosis resistance and tumorigenesis were conferred by Bcl-2 expression. Combining ABT-737 with agents that target Mcl-1 sensitized prostate cancer cell lines with an apoptotic block to cell death in vitro. In mice in vivo, ABT-737 showed single agent efficacy in prostate tumor allografts in which tumor cells are under hypoxic stress. In human prostate cancer tissue, examined using a novel tumor explant system designated Tumor Tissue Assessment for Response to Chemotherapy, combination chemotherapy promoted efficient apoptosis. Thus, rational targeting of both the Bcl-2 and Mcl-1 mechanisms of apoptosis resistance may be therapeutically advantageous for advanced prostate cancer.
Bray
Kevin
K
The Cancer Institute of New Jersey, New Brunswick, NJ 08903-2681, USA.
Chen
Hsin-Yi
HY
Karp
Cristina M
CM
May
Michael
M
Ganesan
Shridar
S
Karantza-Wadsworth
Vassiliki
V
DiPaola
Robert S
RS
White
Eileen
E
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols / Q000008:administration & dosage / Q000494:pharmacology*; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C501332:ABT-737; D001713:Biphenyl Compounds; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53; D017239:Paclitaxel; D002945:Cisplatin