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

Abstract

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.

• Authors: Ryoko Okamoto, Remi Delansorne, Naoki Wakimoto, Ngan B Doan, Tadayuki Akagi, Michelle Shen, Quoc H Ho, Jonathan W Said, H Phillip Koeffler
• Journal: International journal of cancer (Int J Cancer) Vol. 130 Issue 10 Pg. 2464-73 (May 15 2012) ISSN: 1097-0215 [Electronic] United States
• PMID: 21732345 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 UICC.

Chemical References

• Alkynes
• Androgens
• inecalcitol
• Cholecalciferol

Topics

• Alkynes (therapeutic use)
• Androgens (physiology)
• Animals
• Cell Line, Tumor
• Cholecalciferol (analogs & derivatives, therapeutic use)
• Humans
• Male
• Mice
• Neoplasms, Hormone-Dependent (drug therapy)
• Prostatic Neoplasms (drug therapy, metabolism)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays