Abstract 583: Inecalcitol, a 14-epi-analogue of 1,25D3, induces growth inhibition through apoptosis and cell cycle arrest in a squamous cell carcinoma model system

Epidemiological and experimental studies have demonstrated that 1,25D 3 , the active vitamin D metabolite, has broad spectrum anti-tumor activity. However, hypercalcemia may limit its clinical application when administrated inappropriately. An orally available 14-epi-analogue of 1,25D 3 , inecalcitol (19-nor-14-epi-23-yne-1,25-(OH) 2 D 3 , TX522), has shown good clinical tolerance at high and frequent exposure without side effects and hypercalcemia. Therefore, we examined the antitumor activity of inecalcitol in a squamous cell carcinoma (SCC) model system. Inecalcitol at 10 or 100 nM readily induced vitamin D receptor expression in SCC cells. Inecalcitol suppressed SCC cell proliferation in a dose dependent manner as shown by MTT assays. SCC cells underwent G0/G1 cell cycle arrest following inecalcitol treatment, which was accompanied by the induction of p27 protein as shown by immunoblot analysis. Inecalcitol markedly induced apoptosis in SCC cells as examined by annexin V/7AAD staining and DNA fragmentation ELISA assays. The cleavages of caspases 8, 9, and 3 and PARP were observed following inecalcitol treatment in SCC cells. In addition, migration assay revealed that inecalcitol inhibited the motility of SCC cells. Inecalcitol also suppressed the invasion of SCC cells as assessed by Matrigel-based invasion assay. To have a better understanding of the effects of inecalcitol, 1,25D 3 -resistant variant of SCC (SCC-DR) were employed. The above findings were not observed in SCC-DR cells, indicating the critical role of inecalcitol. Our studies suggest that inecalcitol strongly suppress SCC growth through the promotion of apoptosis and cell cycle arrest. Inecalcitol also inhibits SCC migration and invasion. Thus, inecalcitol may be a promising 1,25D 3 analogue for cancer treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 583. doi:10.1158/1538-7445.AM2011-583