Inecalcitol, an analog of 1,25D 3, displays enhanced antitumor activity through the induction of apoptosis in a squamous cell carcinoma model system.

Epidemiological data suggest an important role of vitamin D signaling in cancer development and progression, and experimental studies demonstrate that the active vitamin D metabolite 1α, 25-dihydroxyvitamin D 3 (1,25D 3) has broad spectrum antitumor activity. Hypercalcemia has often been suggested to limit the clinical application of these data. The 14-epi-analog of 1,25D 3, inecalcitol [19-nor-14-epi-23-yne-1,25-(OH) 2D 3; TX522], was developed to have superagonistic antitumor activities but low hypercalcemia potential. We examined the antitumor activity of inecalcitol and the underlying mechanisms in a murine squamous cell carcinoma (SCC) model system. Compared with 1,25D 3, inecalcitol showed enhanced vitamin D receptor (VDR)-mediated transcriptional activity. Inecalcitol suppressed SCC cell proliferation in a dose-dependent manner with an IC 50 value 30 times lower than that of 1,25D 3. Both inecalcitol and 1,25D 3 induced a comparable level of G 0/G 1 cell cycle arrest in SCC cells. The level of apoptosis induced by inecalcitol was markedly higher than that of 1,25D 3. 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 with 1,25D 3. In vivo, inecalcitol inhibits SCC tumor growth in a dose-dependent fashion. Notebly, inecalcitol induced a significantly higher level of apoptosis in the SCC xenograft model. We show that inecalcitol has potent antitumor 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.