Chih-Wun Fang, Division of Pharmacy, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan
Jai-Sing Yang, Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
Jo-Hua Chiang, Department of Nursing, Chung-Jen Junior College of Nursing, Health Sciences and Management, Chiayi, Taiwan
Po-Chuen Shieh, Department of Pharmacy, Tajen University, Pingtung, Taiwan
Fuu-Jen Tsai, School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan
Chia-Wen Tsai, Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
Wen-Shin Chang, Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, TaiwanFollow

Metformin has been used to treat cases of type 2 diabetes mellitus, and mounting studies have shown that metformin can act alone or in synergy with other anticancer agents to achieve anti-cancer efficacies on various types of tumors. However, the role of metformin in either inducing autophagy and cisplatin-resistance of human gastric cancer (GC) cells has never been examined. The study has established a cisplatin-resistant GC cell line and investigated the effects of metformin on inducing autophagy on it. The results demonstrated that treatment with metformin can concentration-dependently suppress the cell viability and cell confluence of cisplatin-resistant GC cells, while having no effects on human primary stomach epithelial cells (HPSEC). For the first time, we found that metformin can significantly increase the acidic vesicular organelles (AVO) level and decrease the acridine orange (AO) level spontaneously in the cisplatin-resistant GC cells. Thus, we further checked the other markers, Atg5, Atg12 and LC3-II, which showed that metformin indeed induced autophagy in the cisplatin-resistant GC cells. In addition, treatment of 3-Methyladenine (3-MA) can significantly rescue the metformin-induced autophagy. At the same time, metformin can induce the alterations of apoptosis-associated signal molecules, such as caspase-3 and caspase-7 activities. Overall, the pilot study provided evidence for metformin induced autophagy in addition to apoptosis, making it as an effective anticancer drug for the therapy of cisplatin-resistant GC. Killing the cisplatin-resistant GC cells with non-toxic metformin via both autophagy and apoptosis might extend its usefulness in our fighting with chemo-resistance of gastric cancer cells.

Fang, Chih-Wun; Yang, Jai-Sing; Chiang, Jo-Hua; Shieh, Po-Chuen; Tsai, Fuu-Jen; Tsai, Chia-Wen; and Chang, Wen-Shin (2023) "Metformin induces autophagy of cisplatin-resistant human gastric cancer cells in addition to apoptosis," BioMedicine: Vol. 13 : Iss. 2 , Article 2.
DOI: 10.37796/2211-8039.1408