Research Article: Efficacy of a Non-Hypercalcemic Vitamin-D2 Derived Anti-Cancer Agent (MT19c) and Inhibition of Fatty Acid Synthesis in an Ovarian Cancer Xenograft Model

Date Published: April 3, 2012

Publisher: Public Library of Science

Author(s): Richard G. Moore, Thilo S. Lange, Katina Robinson, Kyu K. Kim, Alper Uzun, Timothy C. Horan, Nada Kawar, Naohiro Yano, Sharon R. Chu, Quanfu Mao, Laurent Brard, Monique E. DePaepe, James F. Padbury, Leggy A. Arnold, Alexander Brodsky, Tun-Li Shen, Rakesh K. Singh, Olivier Gires. http://doi.org/10.1371/journal.pone.0034443

Abstract

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.

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.

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.

Partial Text

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancies. Early-stage cancers are mostly asymptomatic, and most of the diagnoses at presentation detect established regional or distant metastases [1]. The majority of the patients will experience recurrent disease, as well as resistance to chemotherapeutic agents. 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].

Calcitriol and analogs displayed anti-tumor effects against various cancer types [32]. However, in clinical trials calcitriol and analogs displayed the lack of efficacy and caused hypercalcemia, hyperphosphatemia, and secondary effects such as vascular calcification, nephrocalcinosis or adynamic bone disease [32 and references cited therein]. These adverse outcomes have prompted the development of less hypercalcemic and more efficacious vitamin-D analogs. We developed a new approach to design vitamin-D based molecules that are amenable to small molecule library synthesis and subsequent high-throughput screening. MT19c was designed by a targeted chemical modification of A-ring of vitamin-D2 in just two efficient steps, in contrast to the elaborated synthetic efforts needed for calcitriol or EB1089. We incorporated a nitrogen- and oxygen-rich heterocyclic triazolinedione ring to balance the structure of the molecule in terms of Lipinski’s rule [33]. In a preliminary study, we showed anti-cancer actions of MT19c in cultured ovarian cancer cell models [20].

Source:

http://doi.org/10.1371/journal.pone.0034443

 

Leave a Reply

Your email address will not be published.