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Abstract
Palbociclib and metformin show anticancer efficacy in high grade serous ovarian cancer
Introduction/Background*Alterations in CDK-cyclin signaling pathway lead to cell cycle defects and induce continued cell proliferation, as well as genomic and chromosomal instability. Pharmacological inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) is a well-established anti-cancer treatment in breast cancer and is currently a subject of research in other tumors. Predictive biomarkers for response to CDK4/6 inhibitors include a functional retinoblastoma protein and cyclin D overexpression. According to the data from The Cancer Genome Atlas (TCGA), genomic aberrations that activate cyclin D, are observed in 20-30% of high grade serous ovarian cancer (HGSOC). Currently, there is a lack of data on CDK4/6 inhibition in ovarian cancer.
Metformin is a synthetic biguanide and is widely used as a first line antidiabetic drug. Besides that, anti-cancer efficacy of metformin due to downregulation of cyclin D in cancer cells was reported. Therefore, we hypothesize that metformin could be a potential partner for CDK4/6 inhibitors in cancer treatment and aime to investigate the anti-cancer efficacy of CDK4/6 inhibitor palbociclib in combination with metformin in two-dimensional (2D) and three-dimensional (3D) HGSOC cultures.
Methodology Four ovarian cancer cell lines were treated with palbociclib, or metformin, or combination of both agents. Cell viability was assessed using MTT assays and cell cycle arrest was detected using flow cytometry. Subsequently, the results were validated using 3D-tumor spheroid model.
Result(s)*A significant decrease in cell viability was detected in all four ovarian cancer cell lines under treatment with palbociclib (-99.5% in A2780; -97% in BIN67; -84% in OVCAR3; -61.4% in SKOV6), under treatment with metformin (-85.18%; -75.34%; -86.40%, -62.96%, respectively) and under treatment with the combination of both (-99.6%; -94.9%; -85.8%; -76.9%, respectively). Subsequently, the results were confirmed in 3D tumor spheroid model, where both agents showed synergetic anticancer efficacy. Both agents promoted cell cycle arrest in all four 2D cell lines.
Conclusion*Combination of CDK inhibitor palbociclib and metformin showed high anti-cancer efficacy in 5 ovarian cancer cell lines and in the three-dimensional tumor spheroid model. This effect is probably due to cyclin D-driven cell cycle arrest. Thus, cyclin/CDK pathway represents a novel therapeutic target in ovarian cancer.