Int J Med Sci 2020; 17(16):2416-2426. doi:10.7150/ijms.48635

Research Paper

Metformin reverses the drug resistance of cisplatin in irradiated CNE-1 human nasopharyngeal carcinoma cells through PECAM-1 mediated MRPs down-regulation

Yingming Sun1,2, Xiaochuan Chen3, Yajuan Zhou4, Sufang Qiu3, Yongyang Wu5, Min Xie2, Guofang Zhu2, Shanshan Liang2,6, Heming Li2,6, Dong Zhou2,6, Zaishuang Ju2,6, Fuguang Wang2,6, Fang Han7, Zhe Wang2,6✉, Ruoyu Wang2,6✉

1. Department of Medical and Radiation Oncology, Sanming First Hospital of Fujian Medical University. Sanming 365001, China.
2. Department of Medical Oncology, Affiliated Zhongshan Hospital of Dalian University. Dalian 116001, China.
3. Department of Radiation Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou 350001, China.
4. Department of Radiotherapy, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology. Wuhan, 430074, China.
5. Department of Urology Surgery, Sanming First Hospital of Fujian Medical University. Sanming 365001, China.
6. The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Dalian University, Dalian 116001, P. R. China.
7. Department of Medical Imaging, Affiliated Zhongshan Hospital of Dalian University. Dalian 116001, China.

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Citation:
Sun Y, Chen X, Zhou Y, Qiu S, Wu Y, Xie M, Zhu G, Liang S, Li H, Zhou D, Ju Z, Wang F, Han F, Wang Z, Wang R. Metformin reverses the drug resistance of cisplatin in irradiated CNE-1 human nasopharyngeal carcinoma cells through PECAM-1 mediated MRPs down-regulation. Int J Med Sci 2020; 17(16):2416-2426. doi:10.7150/ijms.48635. Available from http://www.medsci.org/v17p2416.htm

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Abstract

Objective: To explore a way to reverse the drug resistance for irradiated CNE-1 human nasopharyngeal carcinoma cells and try to develop a new high efficacy with low toxicity therapeutic approach. Methods: 300 Gy irradiated the CNE-1 human nasopharyngeal carcinoma cells, and then treated with single-agent cisplatin or metformin, or combination of both drugs. MTT assay and FCM were applied to detect cell viability and apoptosis. Western blot and RT-PCR were used to characterize the protein and mRNA expression after various drug administrations. Results: The results presented single-agent metformin was capable of arresting the tumor growth and inducing apoptosis in irradiated CNE-1 cells and also demonstrated a synergy effect with cisplatin. Furthermore, metformin down-regulates the PECAM-1 expression, which could regulate Multi-drug Resistance-associate Proteins (MRPs) expression leading to cisplatin resistance of irradiated CNE-1 cells. A pan-MRP inhibitor, probenecid, can resecure cisplatin resistance leading by radiation. Conclusions: Metformin, due to its independent effects on PECAM-1, had a unique anti-proliferative effect on irradiated CNE-1 cells. It would be a new therapeutic option to conquer cisplatin resistance for advanced NPC patients after radiotherapy.

Keywords: radiation, cisplatin resistance, metformin, PECAM-1, MRPs.