title: Efficacy of a non-hypercalcemic vitamin-D2 derived anti-cancer agent (MT19c) and inhibition of fatty acid synthesis in an ovarian cancer xenograft model.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Molecular Therapeutics Laboratory, Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants' Hospital of Rhode Island, Alpert Medical School, Brown University, Providence, Rhode Island, United States of America.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Moore
authors.forename: Thilo S
authors.initials: TS
authors.lastname: Lange
authors.forename: Katina
authors.initials: K
authors.lastname: Robinson
authors.forename: Kyu K
authors.initials: KK
authors.lastname: Kim
authors.forename: Alper
authors.initials: A
authors.lastname: Uzun
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Horan
authors.forename: Nada
authors.initials: N
authors.lastname: Kawar
authors.forename: Naohiro
authors.initials: N
authors.lastname: Yano
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Chu
authors.forename: Quanfu
authors.initials: Q
authors.lastname: Mao
authors.forename: Laurent
authors.initials: L
authors.lastname: Brard
authors.forename: Monique E
authors.initials: ME
authors.lastname: DePaepe
authors.forename: James F
authors.initials: JF
authors.lastname: Padbury
authors.forename: Leggy A
authors.initials: LA
authors.lastname: Arnold
authors.forename: Alexander
authors.initials: A
authors.lastname: Brodsky
authors.forename: Tun-Li
authors.initials: TL
authors.lastname: Shen
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Singh
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002118:Calcium / Q000097:blood; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D019343:Citric Acid / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism; D004872:Ergocalciferols / Q000009:adverse effects / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D064429:Fatty Acid Synthases / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis*; D005260:Female; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D006934:Hypercalcemia / Q000139:chemically induced; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008316:Malonyl Coenzyme A / Q000096:biosynthesis; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D012449:Safety; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004872:Ergocalciferols; D005227:Fatty Acids; C568376:MT19c compound; D018167:Receptors, Calcitriol; D019343:Citric Acid; D008316:Malonyl Coenzyme A; D007770:L-Lactate Dehydrogenase; D064429:Fatty Acid Synthases; D066246:ErbB Receptors; D002118:Calcium