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

• Published in: Cell cycle (Georgetown, Tex.) Vol. 12; no. 5; pp. 743 - 752
• Main Authors: Ma, Yingyu, Yu, Wei-Dong, Hidalgo, Alejandro A., Luo, Wei, Delansorne, Remi, Johnson, Candace S., Trump, Donald L.
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.03.2013; Landes Bioscience
• Subjects: 1,25D; Alkynes - pharmacology; Alkynes - therapeutic use; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; apoptosis; Apoptosis - drug effects; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - enzymology; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; Caspases - metabolism; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Cholecalciferol - pharmacology; Cholecalciferol - therapeutic use; Disease Models, Animal; Drug Screening Assays, Antitumor; Enzyme Activation - drug effects; inecalcitol; Inhibitor of Apoptosis Proteins - metabolism; Mice; SCC; Transcription, Genetic - drug effects; TX522; Vitamin D - analogs & derivatives; Vitamin D - pharmacology; X-Linked Inhibitor of Apoptosis Protein - metabolism; inecalcitol; TX522; apoptosis; SCC; 1,25D3
• ISSN: 1538-4101; 1551-4005
• DOI: 10.4161/cc.23846

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 D₃ (1,25D₃) has broad spectrum antitumor 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 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. In vitro, compared with 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 with 1,25D₃. In vivo, inecalcitol inhibits SCC tumor growth in a dose-dependent fashion. Notably, inecalcitol induced a significantly higher level of apoptosis in the SCC xenograft model. While in vitro inecalcitol demonstrates apparent enhanced VDR binding and antiproliferative effects compared to 1,25D₃, in vivo these advantages disappear; at doses of inecalcitol that have equivalent antitumor effects, similar hypercalcemia is seen. This may be explained by the pharmacokinetics of 1,25D₃ vs. inecalcitol and attributed to the much shorter serum half-life of inecalcitol.We show that inecalcitol has potent antitumor activity in the SCC model system, and this is associated with a strong induction of apoptosis. These findings support the further development of inecalcitol in cancer treatment.