Novel Imidazopyridine Derivatives Possess Anti-Tumor Effect on Human Castration-Resistant Prostate Cancer Cells

Abstract

Prostate cancer (PCa) is the second leading cause of cancer-related death afflicting United States males. Most treatments to-date for metastatic PCa include androgen-deprivation therapy and second-generation anti-androgens such as abiraterone acetate and enzalutamide. However, a majority of patients eventually develop resistance to these therapies and relapse into the lethal, castration-resistant form of PCa to which no adequate treatment option remains. Hence, there is an immediate need to develop effective therapeutic agents toward this patient population. Imidazopyridines have recently been shown to possess Akt kinase inhibitory activity; thus in this study, we investigated the inhibitory effect of novel imidazopyridine derivatives HIMP, M-MeI, OMP, and EtOP on different human castration-resistant PCa cells. Among these compounds, HIMP and M-MeI were found to possess selective dose- and time-dependent growth inhibition: they reduced castration-resistant PCa cell proliferation and spared benign prostate epithelial cells. Using LNCaP C-81 cells as the model system, these compounds also reduced colony formation as well as cell adhesion and migration, and M-MeI was the most potent in all studies. Further investigation revealed that while HIMP primarily inhibits PCa cell growth via suppression of PI3K/Akt signaling pathway, M-MeI can inhibit both PI3K/Akt and androgen receptor pathways and arrest cell growth in the G2 phase. Thus, our results indicate the novel compound M-MeI to be a promising candidate for castration-resistant PCa therapy, and future studies investigating the mechanism of imidazopyridine inhibition may aid to the development of effective anti-PCa agents.

Baicalein suppresses the androgen receptor (AR)-mediated prostate cancer progression via inhibiting the AR N-C dimerization and AR-coactivators interaction

“…Despite the effectiveness of ADT and anti-androgen treatment strategies to delay the progression of PCa, many patients still develop the CRPC and thus there is an urgent need for alternative therapeutic targets to AR [ 49 ]. Most CRPC continues to be dependent on transcriptionally active AR for cell proliferation and survival, and it can be activated by several non-androgens factors in the castration androgen environment, suggesting in addition to use antiandrogens to reduce or prevent androgens binding to AR, targeting AR with other factors might present another approach to further suppress these CRPC [ 50 ].…”

Statin derivatives as therapeutic agents for castration-resistant prostate cancer

“…Total cellular lysates were prepared as previously described [30,31]. The protein concentration of the supernatant was determined using a Bio-Rad Bradford protein-assay.…”

“…To determine the compounds’ effects on cell cycle, flow cytometry analysis was conducted as previously described [31]. Briefly, LNCaP C-81 cells were seeded in T25 flasks at a density of 5 × 10 4 cells in regular medium for 3 days, changed to SR medium for 48 hours, and then fed with fresh SR medium containing 20 μM of the specified compound.…”

p66Shc regulates migration of castration-resistant prostate cancer cells

“…Total cellular lysates were prepared as previously described [38–39]. The protein concentration of the supernatant was determined using a Bio-Rad Bradford protein-assay.…”

“…All cells were rinsed with ice-cold HEPES-buffered saline, pH 7.0, harvested via scraping, and lysed in ice-cold lysis buffer containing protease and phosphatase inhibitors. Total cellular lysates were prepared as previously described [38–39]. The protein concentration of the supernatant was determined using a Bio-Rad Bradford protein-assay.…”