Abstract 5533: Anti-proliferative and anti-tumor effects of a novel vitamin D derivative, either alone or in a liposomal formulation in malignancies of kidney, pancreas and prostate

1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) has well-known potential in cancer-therapy; but such a potential is marred by its severe toxicity in pharmacological doses. 1α,25-dihydroxyvitamin D₃-3-bromoacetate (1,25(OH)₂D₃-3-BE) is a novel derivative of 1,25(OH)₂D₃ which enables covalent attachment of 1,25(OH)₂D₃ inside the ligand-binding pocket of nuclear vitamin D receptor, thus increasing the half-life of 1,25(OH)₂D₃ and potentially reducing its therapeutic dose with less toxicity. We have observed that 1,25(OH)₂D₃-3-BE strongly hinders the growth of cells representing malignancies of prostate (androgen-sensitive and androgen-insensitive), pancreas and kidney. However, growth of normal kidney and prostate cells is not affected by this compound. Inhibition of cell-growth by 1,25(OH)₂D₃-3-BE involves hindrance to cell-cycling, and enhancement of apoptosis and autophagy; and includes several mechanisms involving VDR-mediated nuclear pathway and inhibition of Akt-phophorylation. We have also observed that 1,25(OH)₂D₃-3-BE strongly inhibits the growth of prostate and renal tumors in mouse xenograft models. In anticipation of its therapeutic potential we prepared a liposomal formulation of 1,25(OH)₂D₃-3-BE to enhance its efficacy further by potentially preventing its premature degradation and tumor-targeting. We report that liposomal 1,25(OH)₂D₃-3-BE is a significantly stronger growth-inhibiting compound than naked 1,25(OH)₂D₃-3-BE in prostate, kidney and pancreatic cancer cells. This property is also manifested in a mouse xenograft model of androgen-insensitive prostate tumor. In summary, 1,25(OH)₂D₃-3-BE and its liposomal formulation demonstrate a strong translational therapeutic potential in cancers of kidney, pancreas and prostate.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5533.