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.

Inhibition of FOXC2 restores epithelial phenotype and drug sensitivity in prostate cancer cells with stem-cell properties

“…28 Interestingly, loss of FOXC2 expression rendered DU145 cells more susceptible to 100 n M Docetaxel treatment (Figure 3o). Together, these results suggest that FOXC2 expression is necessary and sufficient for the induction of PCaSC attributes associated with loss of AR/PSA expression and emergence of androgen-independence and chemo-resistance.…”

“…For assessing the combined effect of p38MAPK inhibition and the AR antagonist Enzalutamide 27, 46 (SelleckChem, Houston, TX, USA) or the chemotherapeutic Docetaxel 28 (LC Laboratories, Woburn, MA, USA), cells were co-treated with SB203580 and either Enzalutamide/Docetaxel for 7 days. It is important to note that the concentration of SB203580 used to treat PCa cells in our experiments, results in selective inhibition of p38MAPK signaling, as also suggested in the study by Davies et al 45 We did not observe any appreciable changes in the phosphorylation of Akt1, another potential target (data not shown).…”

Pathways and mechanisms of venetoclax resistance

“…[122] In both docetaxel-sensitive and -resistant prostate cancer, BCL-X L seems to be a key determinant of cell survival, as navitoclax, but not venetoclax, significantly augments the anti-tumor efficacy of docetaxel in human prostate cancer cells lines and xenograft mouse models. [123] Conversely, in estrogen receptor-expressing breast cancer, BCL-2 appears to be the crucial target as similar efficacy is observed with venetoclax or ABT-737 in xenografts, despite abundant BCL-X L expression. [124] Furthermore, BH3-mimetics have been shown to counteract tamoxifen-induced endometrial hyperplasia, as well as enhance its anti-tumor efficacy, and to synergize with dual PI3K/mTOR inhibitors in apoptosis induction in this setting.…”

Prostat Kanseri Tedavisinin Geleceği Apoptotik İndükleyicilerde mi?

“…Xenograft fare modelinde, dosetaksel ve ABT-737 kombinasyon terapisinin önemli ölçüde PC3 tümör büyümesini inhibe ettiği görülmüştür. Ayrıca, ABT-263, PC3 hücrelerinde kaspaz-9'u aktive etmesine rağmen, kaspaz-9 inhibisyonu beklenmedik bir şekilde kaspaz-8 bağımlı apoptosisi kolaylaştırmıştır (20). Bu bulgular göstermektedir ki, Bcl-xL inhibisyonu, dosetaksel dirençli PK hücrelerini dosetaksele karşı duyarlı hale getirmekte ve kaspaz-9 inhibe PK hücrelerinin içindeki Bcl-2 ailesi üyelerinin antagonizminin, kaspaz-8 bağımlı hücre ölümünü tetiklediği benzersiz bir apoptotik yolağı açığa çıkarmaktadır.…”