22-Oxa-1,25-Dihydroxyvitamin D3 Efficiently Inhibits Tumor Growth in..

22-Oxa-1,25-Dihydroxyvitamin D3 Efficiently
Inhibits Tumor Growth in Inoculated Mice
and Primary Histoculutre of Cholangiocarcinoma

http://onlinelibrary.wiley.com/doi/10.1002/cncr.25478/pdf

BACKGROUND:
It is well known that 1a,25-Dihydroxyvitamin D3(1,25[OH]2D3) restrains cell proliferation and induces
differentiation and apoptosis in normal and tumor cells. The authors of this report recently demonstrated that
1,25(OH)2D3 effectively inhibits the proliferation of cholangiocarcinoma (CCA) cell lines. The antitumor activity and
the underlying mechanism of 22-oxa-D3, an analog of vitamin D, in mice and in tissue cultures from patients with
CCA were further explored in the current study. METHODS: Cell growth and cell cycle distribution were examined in
CCA cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry. Mice
were injected subcutaneously with 4 106 CCA cells at both flank sides and intraperitoneal injections with phosphate-
buffered saline or 22-oxa-D3(15 lg/kg/day) for 17 days thereafter. Tumors were removed the next day. The
expression levels of cyclin D1 and the cyclin-dependent kinase inhibitor p21 were determined by Western blot analysis
and immunohistochemistry. Growth inhibition of 22-oxa-D3 in fresh tissue samples from patients with CCA was analyzed
by using a histodrug response assay.

RESULTS: 22-Oxa-D3 effectively suppressed the growth of CCA cell lines
in a time-dependent and dose-dependent manner. 22-Oxa-D3 arrested CCA cells at G1 phase to S phase by the suppression
of cyclin D1 expression and the up-regulation of p21. Supplementation of 22-oxa-D3 to CCA-inoculated mice
significantly inhibited tumor growth without hypercalcemia or serious side effects. The treatment also induced cellular
apoptosis in tissue samples from patients with CCA.

CONCLUSIONS: 22-Oxa-D3 effectively suppressed tumor growth
in CCA-inoculated mice and induced cellular apoptosis in tissue samples from patients with CCA. The current data encourage
further investigation of 1,25(OH)2D3 or its analogues as therapeutic agents in the treatment of patients with
CCA. Cancer 2010;116:5535–43. VC 2010 American Cancer Society.