Inecalcitol, an analog of 1a,25(OH)2D3, induces growth arrest of androgen-dependent prostate cancer cells

19-nor-14-epi-23-yne-1,25(OH)2D3 (inecalcitol) is a unique vitamin D3 analog. We evaluated the activity of inecalcitol in a human prostate cancer model system. The analog was 11-fold more potent than 1,25(OH)2D3 in causing 50% clonal growth inhibition of androgen-sensitive human prostate cancer LNCaP cells. Inecalcitol, more than 1,25(OH)2D3, reduced in a dose-dependent manner the expression levels of the transcription factor ETS variant 1 and the serine/threonine protein kinase Pim-1, both of which are upregulated in prostate cancer. Remarkably, dose challenge experiments revealed that inecalcitol maximal tolerated dose (MTD) by intraperitoneal (i.p.) administration was 30 mu g/mouse (1,300 mu g/kg) three times per week, while we previously found that the MTD of 1,25(OH)2D3 is 0.0625 mu g/mouse; therefore, inecalcitol is 480 times less hypercalcemic than 1,25(OH)2D3. Pharmacokinetic studies showed that plasma half-life of inecalcitol were 18.3 min in mice. A xenograft model of LNCaP cells was developed in immunodeficient mice treated with inecalcitol. The tumors of the diluent-treated control mice increased in size but those in the inecalcitol treatment group did not grow. Our data suggest that inecalcitol inhibits androgen-responsive prostate cancer growth in vivo and should be examined either alone or with other chemotherapy in clinical trials in individuals with rising serum prostate-specific antigen after receiving either surgery or irradiation therapy with curative intent.