Metformin in combination with chemotherapy increases apoptosis in gastric cancer cells and counteracts senescence induced by chemotherapy

Vázquez‑Ibarra,Katia Carolina; Sánchez López,Josefina Yoaly; Pineda Razo,Tomás Daniel; Cruz Lozano,José Roberto; Ortiz‑Tamayo,Brenda Guadalupe; Palafox‑Mariscal,Luis Arturo; González Arreola,Rosa María; González‑García,Juan Ramón; Ortiz-Lazareno,Pablo Cesar

doi:10.3892/ol.2024.14590

Metformin in combination with chemotherapy increases apoptosis in gastric cancer cells and counteracts senescence induced by chemotherapy

Authors:
- Katia Carolina Vázquez‑Ibarra
- Josefina Yoaly Sánchez López
- Tomás Daniel Pineda Razo
- José Roberto Cruz Lozano
- Brenda Guadalupe Ortiz‑Tamayo
- Luis Arturo Palafox‑Mariscal
- Rosa María González Arreola
- Juan Ramón González‑García
- Pablo Cesar Ortiz-Lazareno
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Affiliations: Department of Molecular Biology and Genomics, University Center for Health Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, Mexico, Genetic Division, Western Biomedical Research Center, Mexican Social Security Institute, Guadalajara, Jalisco, 44340, Mexico, Medical Oncology Service, Western National Medical Center, Mexican Social Security Institute, Guadalajara, Jalisco 44329, Mexico, Department of Physiology, University Center for Health Sciences, University of Guadalajara, Guadalajara, Jalisco 44340, Mexico, Division of Biological and Environmental Sciences, University Center of Biological and Agricultural Sciences, University of Guadalajara, Guadalajara, Jalisco 44600, Mexico, Immunology Division, Western Biomedical Research Center, Mexican Social Security Institute, Guadalajara, Jalisco 44340, Mexico
Published online on: July 25, 2024 https://doi.org/10.3892/ol.2024.14590
Article Number: 457
Copyright: © Vázquez‑Ibarra et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Gastric cancer (GC) is the fourth leading cause of cancer death in the world, and there is a demand for new therapeutic agents to treat GC. Metformin has been demonstrated to be an antineoplastic agent in some types of cancer; however, it has not been sufficiently valued in treating GC because the effect of metformin in combination with chemotherapy regimens has not yet been evaluated. The present study aimed to evaluate the mechanisms underlying cell death induced by metformin alone or when combined with chemotherapy. The cytogenetic characteristics of the NCI‑N87 cell line were determined by fluorescence in situ hybridization (FISH). To determine viability, the cells were treated with metformin, epirubicin, cisplatin, docetaxel and 5‑fluorouracil (individually and at different concentrations). Subsequently, the cells were treated with metformin alone, and in combination with the chemotherapeutic drugs and the epirubicin + cisplatin + 5‑fluorouracil, docetaxel + cisplatin + 5‑fluorouracil, and cisplatin + 5‑fluorouracil regimens. Cell viability, proliferation and mitochondrial membrane potential (ΔΨm) were analyzed by spectrophotometry. Apoptosis, caspase activity and cell cycle progression were assessed by flow cytometry. Finally, light microscopy was used to evaluate senescence and clonogenicity. The results revealed that metformin, alone and when combined with chemotherapy, increased the proportion of apoptotic cells, promoted the loss of ΔΨm, and induced apoptosis through caspase activity in GC cells. Moreover, metformin decreased cell proliferation. In addition, metformin alone did not induce senescence and it counteracted the effects of chemotherapy‑induced senescence in GC cells. Additionally, metformin, alone and when combined with chemotherapy, decreased the clonogenic capacity of NCI‑N87 GC cells. In conclusion, metformin may increase the effects of chemotherapy on NCI‑N87 cell death and could represent an option to improve the treatment of GC.

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