title: Bcl-2 family inhibition sensitizes human prostate cancer cells to docetaxel and promotes unexpected apoptosis under caspase-9 inhibition.
abstract: Docetaxel (DTX) is a useful chemotherapeutic drug for the treatment of hormone-refractory prostate cancer. However, emergence of DTX resistance has been a therapeutic hurdle. In this study, we investigated the effect of combining DTX with Bcl-2 family inhibitors using human prostate cancer cell lines (PC3, LNCaP, and DU145 cells). PC3 cells were less sensitive to DTX than were the other two cell lines. In contrast to ABT-199, which inhibits Bcl-2 and Bcl-w, both ABT-263 and ABT-737, which inhibit Bcl-2, Bcl-xL, and Bcl-w, significantly augmented the antitumor effect of DTX on PC3 cells. ABT-263 also enhanced the antitumor effect of DTX on a DTX-resistant PC3 variant cell line. The antitumor effect of ABT-263 was due mainly to its inhibitory effect on Bcl-xL. In a xenograft mouse model, DTX and ABT-737 combination therapy significantly inhibited PC3 tumor growth. Interestingly, although ABT-263 activated caspase-9 in PC3 cells, inhibition of caspase-9 unexpectedly promoted ABT-263-induced apoptosis in a caspase-8-dependent manner. This augmented apoptosis was also observed in LNCaP cells. These findings indicate that Bcl-xL inhibition can sensitize DTX-resistant prostate cancer cells to DTX, and they reveal a unique apoptotic pathway in which antagonism of Bcl-2 family members in caspase-9-inhibited prostate cancer cells triggers caspase-8-dependent apoptosis.
authors.affiliation: Department of Immunology, Shimane University Faculty of Medicine, Shimane, Japan. Department of Pharmacy, Shimane University Hospital, Shimane, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tamaki
authors.affiliation: Department of Immunology, Shimane University Faculty of Medicine, Shimane, Japan.
authors.forename: Nanae
authors.initials: N
authors.lastname: Harashima
authors.affiliation: Department of Urology, Shimane University Faculty of Medicine, Shimane, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Hiraki
authors.affiliation: Department of Urology, Shimane University Faculty of Medicine, Shimane, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Arichi
authors.affiliation: Department of Pharmacy, Shimane University Hospital, Shimane, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nishimura
authors.affiliation: Department of Urology, Shimane University Faculty of Medicine, Shimane, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shiina
authors.affiliation: Department of Pharmacy, Shimane University Hospital, Shimane, Japan.
authors.forename: Kohji
authors.initials: K
authors.lastname: Naora
authors.affiliation: Department of Immunology, Shimane University Faculty of Medicine, Shimane, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Harada
mesh_terms: D000814:Aniline Compounds / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000494:pharmacology; D053453:Caspase 9 / Q000378:metabolism*; D061945:Caspase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004357:Drug Synergism; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009596:Nitrophenols / 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* / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D043823:Taxoids / Q000008:administration & dosage / Q000494:pharmacology*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: C501332:ABT-737; D000814:Aniline Compounds; D001713:Biphenyl Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D061945:Caspase Inhibitors; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D043823:Taxoids; D000077143:Docetaxel; D053453:Caspase 9; C579720:venetoclax; C528561:navitoclax