Efficacy of a Non-Hypercalcemic Vitamin-D2 Derived Anti-Cancer Agent MT19c and Inhibition of Fatty Acid Synthesis in an Ovarian Cancer Xenograft ModelReportar como inadecuado




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Background

Numerous vitamin-D analogs exhibited poor response rates, high systemic toxicities and hypercalcemia in human trials to treat cancer. We identified the first non-hypercalcemic anti-cancer vitamin D analog MT19c by altering the A-ring of ergocalciferol. This study describes the therapeutic efficacy and mechanism of action of MT19c in both in vitro and in vivo models.

Methodology-Principal Finding

Antitumor efficacy of MT19c was evaluated in ovarian cancer cell SKOV-3 xenografts in nude mice and a syngenic rat ovarian cancer model. Serum calcium levels of MT19c or calcitriol treated animals were measured. In-silico molecular docking simulation and a cell based VDR reporter assay revealed MT19c–VDR interaction. Genomewide mRNA analysis of MT19c treated tumors identified drug targets which were verified by immunoblotting and microscopy. Quantification of cellular malonyl CoA was carried out by HPLC-MS. A binding study with PPAR-Y receptor was performed. MT19c reduced ovarian cancer growth in xenograft and syngeneic animal models without causing hypercalcemia or acute toxicity. MT19c is a weak vitamin-D receptor VDR antagonist that disrupted the interaction between VDR and coactivator SRC2-3. Genome-wide mRNA analysis and western blot and microscopy of MT19c treated xenograft tumors showed inhibition of fatty acid synthase FASN activity. MT19c reduced cellular levels of malonyl CoA in SKOV-3 cells and inhibited EGFR-phosphoinositol-3kinase PI-3K activity independently of PPAR-gamma protein.

Significance

Antitumor effects of non-hypercalcemic agent MT19c provide a new approach to the design of vitamin-D based anticancer molecules and a rationale for developing MT19c as a therapeutic agent for malignant ovarian tumors by targeting oncogenic de novo lipogenesis.



Autor: Richard G. Moore, Thilo S. Lange, Katina Robinson, Kyu K. Kim, Alper Uzun, Timothy C. Horan, Nada Kawar, Naohiro Yano, Sharon R.

Fuente: http://plos.srce.hr/



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