Bcl-2 family inhibition sensitizes human prostate cancer cells to docetaxel and promotes unexpected apoptosis under caspase-9 inhibition

Hiroki Tamaki; Nanae Harashima; Miho Hiraki; Naoko Arichi; Nobuhiro Nishimura; Hiroaki Shiina; Kohji Naora; Mamoru Harada

doi:10.18632/oncotarget.2550

Bcl-2 family inhibition sensitizes human prostate cancer cells to docetaxel and promotes unexpected apoptosis under caspase-9 inhibition

Oncotarget. 2014 Nov 30;5(22):11399-412. doi: 10.18632/oncotarget.2550.

Authors

Hiroki Tamaki¹, Nanae Harashima², Miho Hiraki³, Naoko Arichi³, Nobuhiro Nishimura⁴, Hiroaki Shiina³, Kohji Naora⁴, Mamoru Harada²

Affiliations

¹ Department of Immunology, Shimane University Faculty of Medicine, Shimane, Japan. Department of Pharmacy, Shimane University Hospital, Shimane, Japan.
² Department of Immunology, Shimane University Faculty of Medicine, Shimane, Japan.
³ Department of Urology, Shimane University Faculty of Medicine, Shimane, Japan.
⁴ Department of Pharmacy, Shimane University Hospital, Shimane, Japan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aniline Compounds / administration & dosage
Aniline Compounds / pharmacology
Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Apoptosis / drug effects
Biphenyl Compounds / administration & dosage
Biphenyl Compounds / pharmacology
Bridged Bicyclo Compounds, Heterocyclic / administration & dosage
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
Caspase 9 / metabolism*
Caspase Inhibitors / administration & dosage
Caspase Inhibitors / pharmacology*
Cell Line, Tumor
Docetaxel
Drug Synergism
Humans
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Nitrophenols / administration & dosage
Nitrophenols / pharmacology
Piperazines / administration & dosage
Piperazines / pharmacology
Prostatic Neoplasms / drug therapy*
Prostatic Neoplasms / genetics
Prostatic Neoplasms / metabolism*
Prostatic Neoplasms / pathology
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
Proto-Oncogene Proteins c-bcl-2 / metabolism
Sulfonamides / administration & dosage
Sulfonamides / pharmacology
Taxoids / administration & dosage
Taxoids / pharmacology*
Transfection
Xenograft Model Antitumor Assays

Substances

ABT-737
Aniline Compounds
Biphenyl Compounds
Bridged Bicyclo Compounds, Heterocyclic
Caspase Inhibitors
Nitrophenols
Piperazines
Proto-Oncogene Proteins c-bcl-2
Sulfonamides
Taxoids
Docetaxel
Caspase 9
venetoclax
navitoclax