Abstract
BackgroundNumerous 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 FindingAntitumor 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.SignificanceAntitumor 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.
Highlights
Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancies
We show that MT19c is a new class of antitumor agent that targets critical components of de novo fatty acid synthesis machinery in ovarian cancer xenograft tumors and ovarian cancer cells
To understand the effect of MT19c on Epidermal growth factor receptor (EGFR) and its downstream signaling cascade in ovarian cancer, we investigated the effect of MT19c on EGFR and PI-3kinase activity in SKOV-3 cells by western blot analysis, microscopy and an in vitro PI-3kinase activity assay
Summary
Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancies. The low survival rate of advanced stage ovarian cancer has made early detection, understanding the etiology of the disease and the targeting of specific characteristic features, as the top priorities in cancer research [1]. Increased de novo fatty-acid synthesis is a hallmark of cancer [2,3]. Normal human tissues use dietary fats for synthesis of new structural lipids, whereas incessantly proliferating cancer cells for unknown reasons avoid utilization of dietary fats and carry out independent de novo fatty acid synthesis to continually provide for membrane production, energy generation and lipid modification of proteins [4]. De novo fatty-acid synthesis involves two key enzymes; acetyl Co-A carboxylase (ACC) and fatty-acid synthase (FASN). Deregulated functions of lipogenic enzymes FASN and ACC involved in de novo fatty-acid synthesis in conjunction with lipolytic PPAR-gamma play an important role in promoting tumor cell survival at multiple levels. This study describes the therapeutic efficacy and mechanism of action of MT19c in both in vitro and in vivo models
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