Metformin Enhances TKI-Afatinib Cytotoxic Effect, Causing Downregulation of Glycolysis, Epithelial–Mesenchymal Transition, and EGFR-Signaling Pathway Activation in Lung Cancer Cells
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 o...
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MDPI AG
2022-03-01
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| Online Access: | https://www.mdpi.com/1424-8247/15/3/381 |
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| author | Pedro Barrios-Bernal Norma Hernandez-Pedro Mario Orozco-Morales Rubí Viedma-Rodríguez José Lucio-Lozada Federico Avila-Moreno Andrés F. Cardona Rafael Rosell Oscar Arrieta |
| author_facet | Pedro Barrios-Bernal Norma Hernandez-Pedro Mario Orozco-Morales Rubí Viedma-Rodríguez José Lucio-Lozada Federico Avila-Moreno Andrés F. Cardona Rafael Rosell Oscar Arrieta |
| author_sort | Pedro Barrios-Bernal |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T12:59:30Z |
| format | Article |
| id | doaj.art-1de0dc7237c34fc6b7e461620507852a |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T12:59:30Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-1de0dc7237c34fc6b7e461620507852a2023-11-30T21:55:18ZengMDPI AGPharmaceuticals1424-82472022-03-0115338110.3390/ph15030381Metformin Enhances TKI-Afatinib Cytotoxic Effect, Causing Downregulation of Glycolysis, Epithelial–Mesenchymal Transition, and EGFR-Signaling Pathway Activation in Lung Cancer CellsPedro Barrios-Bernal0Norma Hernandez-Pedro1Mario Orozco-Morales2Rubí Viedma-Rodríguez3José Lucio-Lozada4Federico Avila-Moreno5Andrés F. Cardona6Rafael Rosell7Oscar Arrieta8Laboratorio de Medicina Personalizada, Thoracic Oncology Unit Instituto Nacional de Cancerología, S.S.A., San Fernando 22 Sección XVI, Tlalpan, Mexico City 14080, MexicoLaboratorio de Medicina Personalizada, Thoracic Oncology Unit Instituto Nacional de Cancerología, S.S.A., San Fernando 22 Sección XVI, Tlalpan, Mexico City 14080, MexicoLaboratorio de Medicina Personalizada, Thoracic Oncology Unit Instituto Nacional de Cancerología, S.S.A., San Fernando 22 Sección XVI, Tlalpan, Mexico City 14080, MexicoUnidad de Morfología y Función, Facultad de Estudios Superiores (FES) Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Mexico City 54090, MexicoLaboratorio de Medicina Personalizada, Thoracic Oncology Unit Instituto Nacional de Cancerología, S.S.A., San Fernando 22 Sección XVI, Tlalpan, Mexico City 14080, MexicoLung Diseases and Cancer Epigenomics Laboratory, Biomedicine Research Unit (UBIMED), Facultad de Estudios Superiores (FES) Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Mexico City 54090, MexicoFoundation for Clinical and Applied Cancer Research—FICMAC/Molecular Oncology and Biology Systems Research Group (Fox-G), Universidad El Bosque, Bogotá 11001, ColombiaCatalan Institute of Oncology, Germans Trias I Pujol Research Institute and Hospital Campus Can Ruti, 8908 Badalona, SpainLaboratorio de Medicina Personalizada, Thoracic Oncology Unit Instituto Nacional de Cancerología, S.S.A., San Fernando 22 Sección XVI, Tlalpan, Mexico City 14080, MexicoThe 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.https://www.mdpi.com/1424-8247/15/3/381lung cancerafatinib–metforminEGFRglycolysisoxidative phosphorylationepithelial–mesenchymal transition |
| spellingShingle | Pedro Barrios-Bernal Norma Hernandez-Pedro Mario Orozco-Morales Rubí Viedma-Rodríguez José Lucio-Lozada Federico Avila-Moreno Andrés F. Cardona Rafael Rosell Oscar Arrieta Metformin Enhances TKI-Afatinib Cytotoxic Effect, Causing Downregulation of Glycolysis, Epithelial–Mesenchymal Transition, and EGFR-Signaling Pathway Activation in Lung Cancer Cells Pharmaceuticals lung cancer afatinib–metformin EGFR glycolysis oxidative phosphorylation epithelial–mesenchymal transition |
| title | Metformin Enhances TKI-Afatinib Cytotoxic Effect, Causing Downregulation of Glycolysis, Epithelial–Mesenchymal Transition, and EGFR-Signaling Pathway Activation in Lung Cancer Cells |
| title_full | Metformin Enhances TKI-Afatinib Cytotoxic Effect, Causing Downregulation of Glycolysis, Epithelial–Mesenchymal Transition, and EGFR-Signaling Pathway Activation in Lung Cancer Cells |
| title_fullStr | Metformin Enhances TKI-Afatinib Cytotoxic Effect, Causing Downregulation of Glycolysis, Epithelial–Mesenchymal Transition, and EGFR-Signaling Pathway Activation in Lung Cancer Cells |
| title_full_unstemmed | Metformin Enhances TKI-Afatinib Cytotoxic Effect, Causing Downregulation of Glycolysis, Epithelial–Mesenchymal Transition, and EGFR-Signaling Pathway Activation in Lung Cancer Cells |
| title_short | Metformin Enhances TKI-Afatinib Cytotoxic Effect, Causing Downregulation of Glycolysis, Epithelial–Mesenchymal Transition, and EGFR-Signaling Pathway Activation in Lung Cancer Cells |
| title_sort | metformin enhances tki afatinib cytotoxic effect causing downregulation of glycolysis epithelial mesenchymal transition and egfr signaling pathway activation in lung cancer cells |
| topic | lung cancer afatinib–metformin EGFR glycolysis oxidative phosphorylation epithelial–mesenchymal transition |
| url | https://www.mdpi.com/1424-8247/15/3/381 |
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