Neoadjuvant metformin added to conventional chemotherapy synergizes anti-proliferative effects in ovarian cancer

Background Ovarian cancer is the leading cause of cancer-related death among women. Complete cytoreductive surgery followed by platinum-taxene chemotherapy has been the gold standard for a long time. Various compounds have been assessed in an attempt to combine them with conventional chemotherapy to...

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Published in:Journal of ovarian research 2020-08, Vol.13 (1), p.1-95, Article 95
Main Authors: Wen, Kuo-Chang, Sung, Pi-Lin, Wu, Alexander T. H, Chou, Ping-Chieh, Lin, Jun-Hung, Huang, Chi-Ying F, Yeung, Sai-Ching J, Lee, Mong-Hong
Format: Article
Language:English
Subjects:
AKT protein
AKT/mTOR pathway
Analysis
Animal models
Antidiabetics
Cancer research
Cell growth
Chemoresistance
Chemotherapy
Clinical trials
Clinically relevant dosage
Cytotoxicity
Datasets
Diabetes mellitus
Diabetes therapy
DNA microarrays
Gene set enrichment analysis
Genomes
Genomics
Kinases
Metformin
Neoadjuvant metformin
Ovarian cancer
Patients
Platinum
Surgery
Surveys
Survival
Synergistic effects
TOR protein
Type 2 diabetes
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Summary:Background Ovarian cancer is the leading cause of cancer-related death among women. Complete cytoreductive surgery followed by platinum-taxene chemotherapy has been the gold standard for a long time. Various compounds have been assessed in an attempt to combine them with conventional chemotherapy to improve survival rates or even overcome chemoresistance. Many studies have shown that an antidiabetic drug, metformin, has cytotoxic activity in different cancer models. However, the synergism of metformin as a neoadjuvant formula plus chemotherapy in clinical trials and basic studies remains unclear for ovarian cancer. Methods We applied two clinical databases to survey metformin use and ovarian cancer survival rate. The Cancer Genome Atlas dataset, an L1000 microarray with Gene Set Enrichment Analysis (GSEA) analysis, Western blot analysis and an animal model were used to study the activity of the AKT/mTOR pathway in response to the synergistic effects of neoadjuvant metformin combined with chemotherapy. Results We found that ovarian cancer patients treated with metformin had significantly longer overall survival than patients treated without metformin. The protein profile induced by low- concentration metformin in ovarian cancer predominantly involved the AKT/mTOR pathway. In combination with chemotherapy, the neoadjuvant metformin protocol showed beneficial synergistic effects in vitro and in vivo. Conclusions This study shows that neoadjuvant metformin at clinically relevant dosages is efficacious in treating ovarian cancer, and the results can be used to guide clinical trials. Keywords: Neoadjuvant metformin, Ovarian cancer, Clinically relevant dosage, AKT/mTOR pathway, Synergistic effects
ISSN:1757-2215
1757-2215
DOI:10.1186/s13048-020-00703-x