Metformin Enhances TKI-Afatinib Cytotoxic Effect, Causing Downregulation of Glycolysis, Epithelial-Mesenchymal Transition, and EGFR-Signaling Pathway Activation in Lung Cancer Cells
Por:
Barrios-Bernal, Pedro, Hernandez-Pedro, Norma, Orozco-Morales, Mario, Viedma-Rodriguez, Rubi, Lucio-Lozada, Jose, Avila-Moreno, Federico, Cardona, Andres F., Rosell, Rafael, Arrieta, Oscar
Publicada:
1 mar 2022
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.
Filiaciones:
Inst Nacl Cancerol, Lab Med Personalizada, Thorac Oncol Unit, SSA, San Fernando 22 Secc 17, Mexico City 14080, DF, Mexico
Univ Nacl Autonoma Mexico, Fac Estudios Super FES Iztacala, Unidad Morfol & Func, Mexico City 54090, DF, Mexico
Univ Nacl Autonoma Mexico, Fac Estudios Super FES Iztacala, Biomed Res Unit UBIMED, Lung Dis & Canc Epigen Lab, Mexico City 54090, DF, Mexico
Univ El Bosque, Fdn Clin & Appl Canc Res FICMAC, Mol Oncol & Biol Syst Res Grp Fox G, Bogota 11001, Colombia
Germans Trias & Pujol Res Inst, Catalan Inst Oncol, Badalona 8908, Spain
Hosp Campus Can Ruti, Badalona 8908, Spain
gold, Green Published, All Open Access, Gold, Green
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