Inecalcitol, an analog of 1α,25(OH) 2 D 3 , induces growth arrest of androgen‐dependent prostate cancer cells

19‐nor‐14‐epi‐23‐yne‐1,25(OH) 2 D 3 (inecalcitol) is a unique vitamin D 3 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) 2 D 3 in causing 50% clonal growth inhibition of androgen‐sensitive human prostate cancer LNCaP cells. Inecalcitol, more than 1,25(OH) 2 D 3 , 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 μg/mouse (1,300 μg/kg) three times per week, while we previously found that the MTD of 1,25(OH) 2 D 3 is 0.0625 μg/mouse; therefore, inecalcitol is 480 times less hypercalcemic than 1,25(OH) 2 D 3 . 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.