Abstract 3434: Inecalcitol, an analogue of 1,25D3, displays enhanced antitumor activity through the induction of apoptosis in a squamous cell carcinoma model system.

Abstract

Abstract Epidemiological data suggest an important role of vitamin D signaling in cancer progression, and experimental studies demonstrate that the active vitamin D metabolite 1α, 25-dihydroxyvitamin D3 (1,25D3) has broad spectrum anti-tumor activity. Hypercalcemia has often been suggested to limit the clinical application of these data. The 14-epi-analog of 1,25D3, inecalcitol (19-nor-14-epi-23-yne-1,25-(OH)2D3; TX522), was developed to have superagonistic anti-tumor activities but low hypercalcemia potential. We examined the anti-tumor activity of inecalcitol and the underlying mechanisms in a murine squamous cell carcinoma (SCC) model system. Compared to 1,25D3, inecalcitol showed enhanced vitamin D receptor (VDR)-mediated transcriptional activity. Inecalcitol suppressed SCC cell proliferation in a dose dependent manner with an IC50 value 30 times lower than that of 1,25D3. Both inecalcitol and 1,25D3 induced a comparable level of G0/G1 cell cycle arrest in SCC cells. The level of apoptosis induced by inecalcitol was markedly higher than that of 1,25D3. Apoptosis was mediated through the activation of the caspase 8/10- caspase 3 pathway. Further, inecalcitol markedly inhibited the mRNA and protein expression of c-IAP1 and XIAP compared to 1,25D3. In vivo, inecalcitol inhibits SCC tumor growth at 80 μg dose without hypercalcemia. Inecalcitol (320 μg) or 1,25D3 (0.312 μg) markedly inhibited tumor growth. Notably, inecalcitol induced a significantly higher level of apoptosis in the SCC xenograft model. We show that inecalcitol has potent anti-tumor activity in the SCC model system and this is associated with a stronger induction of apoptosis. These findings support the further development of inecalcitol in cancer treatment. Citation Format: Yingyu Ma, Wei-Dong Yu, Alejandro A. Hidalgo, Wei Luo, Remi Delansorne, Candace S. Johnson, Donald L. Trump. Inecalcitol, an analogue of 1,25D3, displays enhanced antitumor activity through the induction of apoptosis in a squamous cell carcinoma model system. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3434. doi:10.1158/1538-7445.AM2013-3434