TY - JOUR
T1 - Inecalcitol, an analog of 1,25D3, displays enhanced antitumor activity through the induction of apoptosis in a squamous cell carcinoma model system
AU - Ma, Yingyu
AU - Yu, Wei Dong
AU - Hidalgo, Alejandro A.
AU - Luo, Wei
AU - Delansorne, Remi
AU - Johnson, Candace S.
AU - Trump, Donald L.
N1 - Funding Information:
We thank Dr Josephia R. Muindi for his scientific contribution, Ms Rui-Xian Kong for her excellent technical support and Dr Pamela A. Hershberger for her critical review of the manuscript. This study was supported by NIH/NCI grants CA067267 and CA085142 to Dr Candace S. Johnson, and CA095045 to Dr Donald L. Trump. It was also supported, in part, by the NCI Cancer Center Support Grant to the Roswell Park Cancer Institute (CA016056).
PY - 2013/3/1
Y1 - 2013/3/1
N2 - 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 1,25D 3. 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 1,25D 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 1,25D3. 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.
AB - 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 1,25D 3. 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 1,25D 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 1,25D3. 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.
KW - Apoptosis
KW - Inecalcitol
KW - SCC
KW - TX522
UR - http://www.scopus.com/inward/record.url?scp=84874642956&partnerID=8YFLogxK
U2 - 10.4161/cc.23846
DO - 10.4161/cc.23846
M3 - Article
C2 - 23388458
AN - SCOPUS:84874642956
SN - 1538-4101
VL - 12
SP - 743
EP - 752
JO - Cell Cycle
JF - Cell Cycle
IS - 5
ER -