Combination of Carmustine and Selenite Inhibits EGFR Mediated Growth Signaling in Androgen‐Independent Prostate Cancer Cells

Abstract

Although aberrant androgen receptor (AR) signaling is a central mechanism for castration resistant prostate cancer (CRPC) progression, AR-independent growth signaling is also present in CRPC. The current therapeutic options for patients with CRPC are limited and new drugs are desperately needed to eliminate these crucial growth signaling pathways. We have previously shown that combination of carmustine and selenite effectively induces apoptosis and growth inhibition by targeting AR and AR-variants in CRPC cells. High levels of EGFR expression present in the CRPC cells mediates the cell proliferation via AR-independent growth signaling mechanisms. Therefore, in this study, we investigated whether the combination of carmustine and selenite could inhibit EGFR mediated growth signaling and induce apoptosis in androgen independent-AR negative prostate cancer cells. EGF exposure dose and time dependently increased phospho-EGFR (Tyr845, Tyr1068, and Tyr1045), pAkt (Ser473), and pERK1/2 (Thr204/Tyr202) protein expression levels in AIPC cells. Combination of carmustine and selenite treatment markedly suppressed EGF-stimulated proliferation and survival of AIPC cells and effectively induced apoptosis. The ROS generated by the combination of carmustine and selenite exhibited a strong inhibition on EGF stimulated EGFR and its downstream signaling molecules such as Akt, NF-kB, ERK1/2, and Cyclin D1. Individual agent treatment showed only partial effect. Overall, our findings demonstrated that the combination of carmustine and selenite treatment dramatically inhibits EGFR signaling, proliferation, and induces apoptosis in AIPC cells, suggesting a potential candidate for the treatment of CRPC. The results of the study further suggest that the combination of carmustine and selenite treatment can overcome EGFR mediated AR-independent growth response in CRPC during anti-androgen therapy. J. Cell. Biochem. 118: 4331-4340, 2017. © 2017 Wiley Periodicals, Inc.

Reduced pim‑1 expression increases chemotherapeutic drug sensitivity in human androgen‑independent prostate cancer cells by inducing apoptosis

“…Prostate cancer is a heterogeneous disease in male reproductive system, which consists of androgen-dependent and androgen-independent varieties (22). Androgen deprivation therapy has achieved remarkable results in the treatment of advanced prostate cancer, and hormone therapy has gradually become an important method for the treatment of prostate cancer (23). For androgen-dependent prostate cancer, surgical castration therapy has a certain therapeutic effect (24).…”

A Mini-Review of Reactive Oxygen Species in Urological Cancer: Correlation with NADPH Oxidases, Angiogenesis, and Apoptosis

“…For example, treatment with JS-K, a glutathione S transferase-activated nitric oxide donor prodrug, for 24 h, increased the proportion of apoptotic cells, by inducing ROS production in prostate cancer cells (22RV1, C4-2, LNCaP, and PC-3) [ 140 ]. Interestingly, these authors also showed that the pro-apoptotic effect of JS-K is dose-dependent, and 22RV1 and C4-2 cells were more sensitive than LNCaP and PC-3 cells [ 141 ]. Furthermore, although selenite had a partial pro-apoptotic effect and carmustine showed no apoptosis induction in EGF-stimulated PC-3 cells, combination treatment with carmustine and selenite dramatically induced apoptosis in EGF-stimulated PC-3 cells [ 141 ].…”

“…Interestingly, these authors also showed that the pro-apoptotic effect of JS-K is dose-dependent, and 22RV1 and C4-2 cells were more sensitive than LNCaP and PC-3 cells [ 141 ]. Furthermore, although selenite had a partial pro-apoptotic effect and carmustine showed no apoptosis induction in EGF-stimulated PC-3 cells, combination treatment with carmustine and selenite dramatically induced apoptosis in EGF-stimulated PC-3 cells [ 141 ]. This combination treatment increased ROS production, which triggered apoptosis in 22RV1 and PC-3 cells [ 141 , 142 ].…”

“…Furthermore, although selenite had a partial pro-apoptotic effect and carmustine showed no apoptosis induction in EGF-stimulated PC-3 cells, combination treatment with carmustine and selenite dramatically induced apoptosis in EGF-stimulated PC-3 cells [ 141 ]. This combination treatment increased ROS production, which triggered apoptosis in 22RV1 and PC-3 cells [ 141 , 142 ]. Based on these facts, this combination treatment was speculated to induce apoptosis via ROS production in prostate cancer cells.…”

Combination of Sodium Selenite and Doxorubicin Prodrug Ac-Phe-Lys-PABC-ADM Affects Gastric Cancer Cell Apoptosis in Xenografted Mice

“…In this way, selenite can prevent nonenzymatic formation of parafibrin produced by the tumor cells, thus presenting them as “self” and entering the innate cellular immune system [13, 14]. Combined carmustine and selenite treatment significantly inhibited the transmission and proliferation of epidermal growth factor receptor signals and induced apoptosis in androgen-independent prostate cancer cells, suggesting their potential in castration-resistant prostate cancer therapy [15]. These observations indicating that SS reduced the weight of tumor xenografts are consistent with the results of this study.…”