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

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.

Thamilselvan V ，Menon M ，Stein GS ，Valeriote F ，Thamilselvan S ... -  《-》

Combination of carmustine and selenite effectively inhibits tumor growth by targeting androgen receptor, androgen receptor-variants, and Akt in preclinical models: New hope for patients with castration resistant prostate cancer.

Despite established androgen receptor (AR) antagonists, AR/AR-variants signaling remain a major obstacle for the successful treatment of castration resistant prostate cancer (CRPC). In addition, CRPC cells adapt to survive via AR-independent pathways to escape next generation therapies. Therefore, there is an urgent need for drugs that can target these signaling pathways in CRPC. In this study, we sought to determine whether carmustine and selenite in combination could induce apoptosis and inhibit growth of CRPC in-vitro and in-vivo. CRPC (22Rv1, VCaP, and PC-3) cell lines in culture and xenograft mouse were used. Combination of carmustine and selenite treatment significantly increased reactive oxygen species, apoptosis and growth inhibition in CRPC cells with down regulation of anti-apoptotic (Bcl-2 and Mcl-1) and proliferative proteins (c-Myc and cyclin-D1). This effect was associated with complete reduction of AR/AR-variants, AR-V7, PSA and significant induction of p27Kip1. Combination treatment substantially abolished phospho-Akt, phospho-GSK-3β, and anchorage-independent growth in AR-positive and AR-negative cells. Consistent with in-vitro results, combination treatment effectively induced apoptosis and completely inhibited xenograft tumor growth and markedly reduced AR/AR-variants, AR-V7, PSA, and Bcl-2 in xenograft tumors without causing genotoxicity in host mice. Individual agent treatment showed only partial effect. The combination treatment showed a significant synergistic effect. The present study is the first to demonstrate that the combination of carmustine and selenite treatment completely suppressed CRPC tumor growth by reducing AR/AR-variants and Akt signaling. Our findings suggest that the combination of carmustine and selenite could constitute a promising next-generation therapy for successful treatment of patients with CRPC.

Thamilselvan V ，Menon M ，Thamilselvan S 《-》

Grape seed extract inhibits EGF-induced and constitutively active mitogenic signaling but activates JNK in human prostate carcinoma DU145 cells: possible role in antiproliferation and apoptosis.

Tyagi A ，Agarwal R ，Agarwal C 《ONCOGENE》

Isorhapontigenin induced cell growth inhibition and apoptosis by targeting EGFR-related pathways in prostate cancer.

Isorhapontigenin (ISO), a naturally phytopolyphenol compound existing in Chinese herb, apples, and various vegetables, has attracted extensive interest in recent years for its diverse pharmacological characteristics. Increasing evidences reveal that ISO can inhibit cancer cell growth by induced apoptosis, however, the molecular mechanisms is not fully understood. In this study, we found for the first time that ISO apparently induced cell growth inhibition and apoptosis by targeting EGFR and its downstream signal pathways in prostate cancer (PCa) cells both in vitro and in vivo, whereas no obviously effect on normal prostate cells. From the results, we found that ISO competitively targeted EGFR with EGF and inhibited EGFR auto-phosphorylation, and then decreased the levels of p-Erk1/2, p-PI3 K, and p-AKT, and further induced down-regulation of p-FOXO1 and promoted FOXO1 nuclear translocation; and finally resulted in a significantly up-regulation of Bim/p21/27/Bax/cleaved Caspase-3/cleaved PARP-1 and a markedly down-regulation of Sp1/Bcl-2/XIAP/Cyclin D1. Moreover, our experimental data demonstrated that treatment of ISO decreased protein level of AR via both inhibiting the expression of AR gene and promoting the ubiquitination/degradation of AR proteins in proteasome. In vivo, we also found that ISO inhibited the growth of subcutaneous xenotransplanted tumor in nude mice by inducing PCa cell growth inhibition and apoptosis. Taken together, all findings here clearly implicated that EGFR-related signal pathways, including EGFR-PI3K-Akt and EGFR-Erk1/2 pathways, were involved in ISO-induced cell growth inhibition and apoptosis in PCa cells, providing a more solid theoretical basis for the application of ISO to treat patients with prostate cancer in clinic.

Zhu C ，Zhu Q ，Wu Z ，Yin Y ，Kang D ，Lu S ，Liu P ... -  《-》

Activation of mitogen-activated protein kinase pathway by the antiandrogen hydroxyflutamide in androgen receptor-negative prostate cancer cells.

Lee YF ，Lin WJ ，Huang J ，Messing EM ，Chan FL ，Wilding G ，Chang C ... -  《CANCER RESEARCH》