Synergistic anti-cancer effects of metformin and cisplatin on YD-9 oral squamous carcinoma cells via AMPK pathway

Paras Man Pradhan; Young-Hee Lee; Sungil Jang; Ho-Keun Yi

doi:10.1590/

Authors

Paras Man Pradhan Jeonbuk National University. Institute of Oral Bioscience. School of Dentistry, Department of Oral Biochemistry https://orcid.org/0009-0003-0274-1857
Young-Hee Lee Jeonbuk National University. Institute of Oral Bioscience. School of Dentistry. Department of Oral Biochemistry https://orcid.org/0000-0002-8081-4367
Sungil Jang Jeonbuk National University. Institute of Oral Bioscience. School of Dentistry. Department of Oral Biochemistry https://orcid.org/0000-0001-6144-6899
Ho-Keun Yi Jeonbuk National University. Institute of Oral Bioscience. School of Dentistry. Department of Oral Biochemistry https://orcid.org/0000-0003-4403-3827

DOI:

https://doi.org/10.1590/

Keywords:

Drug therapy, Apoptosis, Reactive oxygen species, Epithelial-mesenchymal transition, Extracellular signal-regulated kinase

Abstract

Objective This study evaluated whether hypoglycemic drug metformin enhances the anti-cancer effects of cisplatin in YD-9 cells. Methodology YD-9 cells, derived from oral mucosal squamous cell carcinoma of oral mucosa, were used to assess the combined effects of metformin and cisplatin by means of MTT assay, live and dead cell staining, and colony formation assays to evaluate cell viability and proliferation. Reactive oxygen species level was measured using a Muse cell analyzer. Apoptosis, epithelial-mesenchymal transition, and related molecular pathways were analyzed by western blot. Wound healing assays and Transwell migration assays examined cell migration, whereas monophosphate-activated protein kinase inhibitor Compound C, was utilized to investigate the AMPK pathway. Results Sequential treatment of YD-9 cells with metformin and cisplatin resulted in decreased cell viability and proliferation, increased ROS levels, and elevated apoptosis compared with the individual drugs. Moreover, the treatment inhibited EMT, wound healing, and cell migration. These results correlated with increased AMPK phosphorylation, a key regulator of cellular energy homeostasis. Introduction of Compound C pre-treatment upregulated N-cadherin and α-smooth muscle actin along with enhanced cell migration. Conclusion This study found synergism in anti-cancer effects between metformin and cisplatin. Additionally, introduction of Compound C confirmed that EMT inhibition is AMPK dependent. These findings indicate the potential use of metformin as an adjunct drug in anti-cancer treatments, warranting further investigation.

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