A major challenge in the management of patients with prostate cancer is the treatment of hormone refractory tumors (HRPC), a hallmark of incurable and lethal prostate cancer progression. Novel strategies are needed to improve the treatment of prostate cancer and ultimately increase the survival of prostate cancer patients. Troglitazone, a peroxisome proliferators-activated receptor γ (PPARγ) agonist, has been reported to repress PSA expression and induce apoptosis in prostate cancer cells. Our data indicated that troglitazone has potential to inhibit the function of AR and Bcl-xL/Bcl-2, which are both critical survival signals involved in the progression of HRPC.
In this study, we start from demonstrating that downregulate of androgen-stimulated PSA expression by troglitazone is through a PPARγ independent mechanism. The evidence showed that the inhibition of PSA expression is mediated primarily through the interference of AR recruitment to the AREI and AREII within the PSA promoter region. Although the effect of down-regulation of PSA didn’t contribute to the antitumor activity, it is noteworthy that troglitazone and delta2TG at doses higher than 30 uM were able to inhibit AR expression and induced apoptosis in LNCaP cells. By screening against a thiazolidinedione-based library, we identified a PPARγ inactive derivative, STG28, which exhibited higher potency on AR repression. Evidence indicates that these troglitazone derivatives mediated transcriptional repression of AR by facilitating ubiquitin-dependent proteasomal degradation of the transcriptional factor Sp1.
Furthermore, we have demonstrated that Bcl-xL overexpression provides a distinctive survival mechanism that protects PC-3 cells from apoptosis signals emanating from PI3K inhibition. Considering the pivotal role of Bcl-xL and Bcl-2 in the development of androgen independent prostate cancer, we discovered that troglitazone has ability to inhibit the function of Bcl-xL and Bcl-2 by disrupting the BH3 domain-mediated interactions with pro-apoptotic Bcl-2 members. Troglitazone derivatives that lack activity in PPARγ activation have been utilized to demonstrate the proof of principle and modified to design more potent agents on inhibition of Bcl-xL/Bcl-2.
Together, we have developed two novel class small molecules inhibitors against AR and Bcl-xL/Bcl-2, which are potential targets to inhibit the progression of hormone refractory prostate cancer.