Metformin Enhances TKI-Afatinib Cytotoxic Effect, Causing Downregulation of Glycolysis, Epithelial–Mesenchymal Transition, and EGFR-Signaling Pathway Activation in Lung Cancer Cells

Autores organización

• 

  Andres Felipe Cardona Mendoza

  Autor

Autores

• Barrios-Bernal P
• Hernandez-Pedro N
• Orozco-Morales M
• Viedma-Rodríguez R
• Lucio-Lozada J
• Avila-Moreno F
• Rosell R
• Arrieta O

Grupos de investigación

• Grupo de Inmunología celular y molecular Universidad El Bosque (InmuBo)

  Investigador

  Maria Consuelo Romero Sanchez

Resumen

The combination of metformin and TKIs for non-small cell lung cancer has been proposed as a strategy to overcome resistance of neoplastic cells induced by several molecular mechanisms. This study sought to investigate the effects of a second generation TKI afatinib, metformin, or their combination on three adenocarcinoma lung cancer cell lines with different EGFRmutation status. A549, H1975, and HCC827 cell lines were treated with afatinib, metformin, and their combination for 72 h. Afterwards, several parameters were assessed including cytotoxicity, interactions, apoptosis, and EGFR protein levels at the cell membrane and several glycolytic, oxidative phosphorylation (OXPHOS), and EMT expression markers. All cell lines showed additive to synergic interactions for the induction of cytotoxicity caused by the tested combination, as well as an improved pro-apoptotic effect. This effect was accompanied by downregulation of glycolytic, EMT markers, a significant decrease in glucose uptake, extracellular lactate, and a tendency towards increased OXPHOS subunits expression. Interestingly, we observed a better response to the combined therapy in lung cancer cell lines A549 and H1975, which normally have low affinity for TKI treatment. Findings from this study suggest a sensitization to afatinib therapy by metformin in TKI-resistant lung cancer cells, as well as a reduction in cellular glycolytic phenotype. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

• afatinib; lactic acid; metformin; uvomorulin; A-549 cell line; apoptosis; Article; cell membrane; cell viability; clinical effectiveness; controlled study; cytotoxicity; down regulation; drug effect; drug efficacy; drug mechanism; drug response; EGFR signaling; epithelial mesenchymal transition; glucose transport; glycolysis; HCC827 cell line; lung cancer cell line; NCI-H1975 cell line; oxidative phosphorylation; phenotype; protein expression