Reversible lysine-specific demethylase 1 antagonist HCI-2509 inhibits growth and decreases c-MYC in castration- and docetaxel-resistant prostate cancer cells

Background:lysine-specific demethylase 1 (lsd1 or kdm1a) overexpression correlates with poor survival and castration resistance in prostate cancer. lsd1 is a coregulator of ligand-independent androgen receptor signaling promoting c-myc expression. we examined the antitumor efficacy of lsd1 inhibition with hci-2509 in advanced stages of prostate cancer.methods:cell survival, colony formation, histone methylation, c-myc level, c-myc expression, cell cycle changes and in vivo efficacy were studied in castration-resistant prostate cancer cells upon treatment with hci-2509. in vitro combination studies, using hci-2509 and docetaxel, were performed to assess the synergy. cell survival, colony formation, histone methylation and c-myc levels were studied in docetaxel-resistant prostate cancer cells treated with hci-2509.results:hci-2509 is cytotoxic and inhibits colony formation in castration-resistant prostate cancer cells. hci-2509 treatment causes a dose-dependent increase in h3k9me2 (histone h3lysine 9) levels, a decrease in c-myc protein, inhibition of c-myc expression and accumulation in the g0/g1 phase of the cell cycle in these cells. pc3 xenografts in mice have a significant reduction in tumor burden upon treatment with hci-2509 with no associated myelotoxicity or weight loss. more synergy is noted at sub-ic50 (half-maximal inhibitory concentration) doses of docetaxel and hci-2509 in pc3 cells than in du145 cells. hci-2509 has growth-inhibitory efficacy and decreases the c-myc level in docetaxel-resistant prostate cancer cells.conclusions:lsd1 inhibition with hci-2509 decreases the c-myc level in poorly differentiated prostate cancer cell lines and has a therapeutic potential in castration- and docetaxel-resistant prostate cancer.