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
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.
Oncol Lett. 2024 Jul 25;28(4):457. doi: 10.3892/ol.2024.14590. eCollection 2024 Oct.
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 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.
胃癌（GC）是全球癌症死亡的第四大主要原因，因此需要新的治疗药物来治疗GC。二甲双胍已被证明在某些类型的癌症中是一种抗肿瘤药物；然而，由于二甲双胍与化疗方案联合使用的效果尚未得到评估，其在治疗GC方面尚未得到充分重视。本研究旨在评估二甲双胍单独使用或与化疗联合使用时诱导细胞死亡的机制。通过荧光杂交（FISH）确定NCI-N87细胞系的细胞遗传学特征。为了确定细胞活力，用二甲双胍、表柔比星、顺铂、多西他赛和5-氟尿嘧啶（单独使用及不同浓度）处理细胞。随后，单独用二甲双胍处理细胞，并与化疗药物以及表柔比星+顺铂+5-氟尿嘧啶、多西他赛+顺铂+5-氟尿嘧啶和顺铂+5-氟尿嘧啶方案联合使用。通过分光光度法分析细胞活力、增殖和线粒体膜电位（ΔΨm）。通过流式细胞术评估细胞凋亡、半胱天冬酶活性和细胞周期进程。最后，用光学显微镜评估衰老和克隆形成能力。结果显示，二甲双胍单独使用或与化疗联合使用时，可增加GC细胞中凋亡细胞的比例，促进ΔΨm的丧失，并通过半胱天冬酶活性诱导凋亡。此外，二甲双胍可降低细胞增殖。此外，单独使用二甲双胍不会诱导衰老，并且可抵消GC细胞中化疗诱导的衰老作用。此外，二甲双胍单独使用或与化疗联合使用时，可降低NCI-N87 GC细胞的克隆形成能力。总之，二甲双胍可能会增强化疗对NCI-N87细胞死亡的作用，可能是改善GC治疗的一种选择。
