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Synergistic effect of MEK inhibitor and metformin combination in low grade serous ovarian cancer.
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- Additional Information
- Source:
Publisher: Academic Press Country of Publication: United States NLM ID: 0365304 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1095-6859 (Electronic) Linking ISSN: 00908258 NLM ISO Abbreviation: Gynecol Oncol Subsets: MEDLINE
- Publication Information:
Original Publication: New York, Academic Press.
- Subject Terms:
Antimetabolites/
*pharmacology ;
Cell Proliferation/
*drug effects ;
Deoxyglucose/
*pharmacology ;
Hypoglycemic Agents/
*pharmacology ;
Metformin/
*pharmacology ;
Neoplasms, Cystic, Mucinous, and Serous/
*drug therapy ;
Neoplasms, Glandular and Epithelial/
*drug therapy ;
Ovarian Neoplasms/
*drug therapy ;
Protein Kinase Inhibitors/
*pharmacology ;
Pyridones/
*pharmacology ;
Pyrimidinones/
*pharmacology;
AMP-Activated Protein Kinases/
drug effects ;
AMP-Activated Protein Kinases/
metabolism ;
Antimetabolites/
therapeutic use ;
Blotting, Western ;
Carcinoma, Ovarian Epithelial ;
Cell Line, Tumor ;
Deoxyglucose/
therapeutic use ;
Drug Synergism ;
Drug Therapy, Combination ;
Female ;
Humans ;
Hypoglycemic Agents/
therapeutic use ;
Metformin/
therapeutic use ;
Neoplasm Grading ;
Neoplasms, Cystic, Mucinous, and Serous/
genetics ;
Neoplasms, Glandular and Epithelial/
genetics ;
Ovarian Neoplasms/
genetics ;
Protein Kinase Inhibitors/
therapeutic use ;
Pyridones/
therapeutic use ;
Pyrimidinones/
therapeutic use ;
Signal Transduction ;
ras Proteins/
genetics - Abstract:
Objective: Low-grade serous ovarian cancer (LGSOC) constitutes 5-8% of epithelial ovarian cancers and is refractory to chemotherapy. We and others have shown metformin to cause significant growth inhibition in high-grade ovarian cancer both in vitro and in vivo. Here, we aimed to analyze if metformin was effective in inhibiting proliferation of LGSOC alone and in combination with MEK inhibitor.
Methods: Three LGSOC lines (VOA1056, VOA1312 and VOA5646) were treated with metformin, trametinib or 2-deoxyglucose (2DG) alone or in combination with metformin. Proliferation was measured by MTT assay over a period of four days. Protein expression was measured by western blotting. Seahorse Analyzer was used to measure effect of metformin on glycolysis and mitochondrial respiration.
Results: All LGSOC cell lines showed significant inhibition with metformin in a dose- and time-dependent manner. Trametinib significantly inhibited the growth of Ras mutated LGSOC lines (VOA1312 and VOA1056), while VOA5646 cells without RAS mutation did not show any response. Metformin and trametinib combination showed synergistic inhibition of RAS mutated VOA1312 and VOA1056 cells, but not for non-Ras mutated VOA5646 cells. Metformin and trametinib increased phosphorylated AMPK expression in LGSOC lines with combination showing stronger expression. Trametinib decreased 42/44 mitogen activated kinase phosphorylation in all cell lines, while metformin and combination had no significant effect. 2-DG significantly inhibited glycolysis in all LGSOC lines and combination with metformin showed synergistic inhibitory effect.
Conclusions: Metformin alone or in combination with MEK and glycolytic inhibitors may be a potential therapy for LGSOC, a cancer that is indolent but chemo-resistant.
(Copyright © 2017 Elsevier Inc. All rights reserved.)
- Accession Number:
0 (Antimetabolites)
0 (Hypoglycemic Agents)
0 (Protein Kinase Inhibitors)
0 (Pyridones)
0 (Pyrimidinones)
33E86K87QN (trametinib)
9100L32L2N (Metformin)
9G2MP84A8W (Deoxyglucose)
EC 2.7.11.31 (AMP-Activated Protein Kinases)
EC 3.6.5.2 (ras Proteins)
- Publication Date:
Date Created: 20170527 Date Completed: 20170724 Latest Revision: 20190221
- Publication Date:
20231215
- Accession Number:
10.1016/j.ygyno.2017.05.019
- Accession Number:
28545687
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