Efficacy of a non-hypercalcemic vitamin-D2 derived anti-cancer agent (MT19c) and inhibition of fatty acid synthesis in an ovarian cancer xenograft model

Autor: Quanfu Mao, Katina Robinson, Leggy A. Arnold, Tun-Li Shen, Alexander S. Brodsky, James F. Padbury, Naohiro Yano, Kyu K. Kim, Timothy C. Horan, Alper Uzun, Laurent Brard, N. Kawar, Sharon Chu, Monique E. DePaepe, Thilo S. Lange, Rakesh K. Singh, Richard G. Moore
Jazyk: angličtina
Rok vydání: 2012
Předmět:
Cancer Treatment
Gene Expression
lcsh:Medicine
Carcinoma
Ovarian Epithelial
Biochemistry
Calcitriol receptor
Mice
Molecular Cell Biology
Basic Cancer Research
Homeostasis
Neoplasms
Glandular and Epithelial
Clinical Trials (Cancer Treatment)
lcsh:Science
Membrane Potential
Mitochondrial
Ovarian Neoplasms
Multidisciplinary
Cell Death
biology
Chemistry
Fatty Acids
Hormonal Therapy
Obstetrics and Gynecology
Genomics
ErbB Receptors
Malonyl Coenzyme A
Fatty acid synthase
Oncology
Ergocalciferols
Medicine
Syngenic
Oncology Agents
Female
Antiangiogenesis Therapy
Safety
medicine.symptom
Cancer Prevention
Research Article
Signal Transduction
medicine.drug
Drugs and Devices
medicine.medical_specialty
Calcitriol
Clinical Research Design
Molecular Sequence Data
Down-Regulation
Antineoplastic Agents
Molecular Dynamics Simulation
Citric Acid
In vivo
Cell Line
Tumor
Internal medicine
Chemical Biology
medicine
Animals
Humans
Amino Acid Sequence
Biology
L-Lactate Dehydrogenase
Organic Chemistry
lcsh:R
Computational Biology
Cancers and Neoplasms
Cancer
Chemotherapy and Drug Treatment
medicine.disease
Xenograft Model Antitumor Assays
Rats
Endocrinology
Mechanism of action
Metabolic Disorders
Hypercalcemia
biology.protein
Cancer research
Receptors
Calcitriol
Calcium
lcsh:Q
Medicinal Chemistry
Fatty Acid Synthases
Genome Expression Analysis
Ovarian cancer
Zdroj: PLoS ONE, Vol 7, Iss 4, p e34443 (2012)
PLoS ONE
ISSN: 1932-6203
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: