Previously, we reported that 6-(3,4-dihydro-1H-isoquinolin-2-yl)-N-(6-methylpyridin-2-yl) nicotinamide (DIMN) analogues inhibited the growth of prostate cancer cells as an anti-androgenic compound. In the present study, we evaluated cytotoxic effects of these DIMN derivatives and found that DIMN-26 most potently inhibited the proliferation of the LNCap-LN3 androgen-dependent and DU145 androgen-independent prostate cancer cells through induction of G2/M phase cell cycle arrest and subsequent apoptosis. The G2/M phase arrest was found due to increases in the activation of cdc2 (also known as cyclin-dependent kinase 1, CDK1)/cyclin B1 complex. DIMN-26 also induced apoptosis in LNCap-LN3 and DU145 prostate cancer cells through activation of caspase-3, -8, and -9, and cleavage of poly(ADP-ribose) polymerase-1 (PARP-1). In addition, DIMN-26 caused the dephosphorylation and mitochondrial accumulation of Bad protein and induced the loss of mitochondria membrane potential, consequently releasing cytochrome c into the cytosol of the cell. Furthermore, overexpression of AKT protein significantly reduced DIMN-26-induced PARP-1 cleavage and p-Bad decrease and cdc2 activation. In addition, DIMN-26 inhibited the 5α-dihydrotestosterone (DHT)-induced cell growth and proliferation and nuclear translocation and transcriptional activities of androgen receptor (AR) in LNCap-LN3 prostate cancer cells. Consistent with these findings, DIMN-26 significantly inhibited the DHT-induced expression of AR-response genes (ARGs), such as prostate-specific antigen (PSA), AR, β2-microglobulin (B2M), selenoprotein P (SEPP1), and ste20-related proline-alanine-rich kinase (SPAK) in LNCap-LN3 prostate cancer cells. Taken together, these results suggest that DIMN-26 plays a therapeutic role not only in induction of G2/M arrest and apoptosis but also in suppression of androgen receptor signaling in androgen-dependent and androgen-independent prostate cancer cells.
Keywords: 6-(3,4-dihydro-1H-isoquinoline-2-yl)-N-(6 methoxypyridine-2-yl) nicotinamide-26; AKT; Androgen receptor; Apoptosis; G(2)/M arrest; Prostate cancer.
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