Inecalcitol, an analog of 1,25D₃, displays enhanced antitumor activity through the induction of apoptosis in a squamous cell carcinoma model system

• DOI: 10.4161/cc.23846
• Publication Date: 2013-02-22T10:37:03Z
• Authors: Yingyu Ma; Wei-Dong Yu; Alejandro A. Hidalgo; Wei Luo; Remi Delansorne; Candace S. Johnson; Donald L. Trump
• Keywords: Transcription, Genetic; Antineoplastic Agents; Apoptosis; X-Linked Inhibitor of Apoptosis Protein; Cell Cycle Checkpoints; Inhibitor of Apoptosis Proteins; 3. Good health; Enzyme Activation; Disease Models, Animal; Mice; 03 medical and health sciences; 0302 clinical medicine; Alkynes; Caspases; Cell Line, Tumor; Carcinoma, Squamous Cell; Animals; Drug Screening Assays, Antitumor; Vitamin D; Cell Proliferation; Cholecalciferol

Epidemiological data suggest an important role of vitamin D signaling in cancer development and progression, experimental studies demonstrate that the active metabolite 1α, 25-dihydroxyvitamin D₃ (1,25D₃) has broad spectrum antitumor activity. Hypercalcemia often been suggested to limit clinical application these data. The 14-epi-analog 1,25D₃, inecalcitol [19-nor-14-epi-23-yne-1,25-(OH)₂D₃; TX522], was developed have superagonistic activities but low hypercalcemia potential. We examined activity underlying mechanisms a murine squamous cell carcinoma (SCC) model system. In vitro, compared with showed enhanced receptor (VDR)-mediated transcriptional Inecalcitol suppressed SCC proliferation dose-dependent manner IC50 value 30 times lower than 1,25D₃. Both 1,25D₃ induced comparable level G0/G₁ cycle arrest cells. apoptosis by markedly higher Apoptosis mediated through activation caspase 8/10- 3 pathway. Further, inhibited mRNA protein expression c-IAP1 XIAP vivo, inhibits tumor growth fashion. Notably, significantly xenograft model. While vitro demonstrates apparent VDR binding antiproliferative effects vivo advantages disappear; at doses equivalent effects, similar is seen. This may be explained pharmacokinetics vs. attributed much shorter serum half-life inecalcitol.We show potent system, this associated strong induction apoptosis. These findings support further treatment.