J Cancer 2020; 11(24):7312-7319. doi:10.7150/jca.46630

Research Paper

Amide-type local anesthetics may suppress tumor cell proliferation and sensitize Human Hepatocellular Carcinoma Cells to Cisplatin via upregulation of RASSF1A expression and demethylation

Dongtai Chen1*, Yan Yan1,2*, Jingdun Xie1*, Jiahao Pan1, Yonghua Chen3, Qiang Li1, Yunfei Yuan4, Weian Zeng1✉, Wei Xing1✉

1. Department of Anesthesiology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
2. Department of Anesthesiology, Huizhou Municipal Central Hospital, Huizhou 516001, China.
3. Department of Anesthesiology, Peking University Shenzhen Hospital, Shenzhen 518000, China.
4. Department of Hepatobiliary Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
*These authors equally contributed to this work.

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Citation:
Chen D, Yan Y, Xie J, Pan J, Chen Y, Li Q, Yuan Y, Zeng W, Xing W. Amide-type local anesthetics may suppress tumor cell proliferation and sensitize Human Hepatocellular Carcinoma Cells to Cisplatin via upregulation of RASSF1A expression and demethylation. J Cancer 2020; 11(24):7312-7319. doi:10.7150/jca.46630. Available from https://www.jcancer.org/v11p7312.htm

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Abstract

Background: It has been reported that local anesthetics are toxic to various types of cells. Furthermore, several local anesthetics have been confirmed to exert demethylation effects and regulate the proliferation of human cancer cells. Our previous findings suggest that lidocaine may exert potential antitumor activity and enhance the sensitivity of cisplatin to hepatocellular carcinoma in vitro and in vivo. A recent study proved that lidocaine sensitizes breast cancer cells to cisplatin via upregulation of RASSF1A, a promotor of tumor suppressive gene (TSG) demethylation. We sought to determine whether amide-type local anesthetics (lidocaine, ropivacaine and bupivacaine) exert growth-inhibitory effects on human hepatoma cells and to determine whether amide-type local anesthetics sensitize human hepatoma cells to cisplatin-mediated cytotoxicity via upregulation of RASSF1A expression.

Methods: Human hepatoma cell lines HepG2 and BEL-7402 were incubated with lidocaine, ropivacaine and bupivacaine. The viability of local anesthetic-treated cells with or without cisplatin was investigated. Further, we evaluated RASSF1A expression after treatment of HepG2 and BEL-7402 cells with three local anesthetics and determined the influence of RASSF1A expression on the toxicity of cisplatin to these cells.

Results: The viability of HepG2 and BEL-7402 cells was significantly decreased by treatment with amide-type local anesthetics (lidocaine, ropivacaine and bupivacaine). In these cells, the combination treatment with cisplatin and local anesthetics exhibited a stronger reduction in viability. Lidocaine, ropivacaine and bupivacaine promoted a significant increase in RASSF1A expression and a decrease in RASSF1A methylation. The combined treatment with both local anesthetics and cisplatin resulted in a significantly lower level of HepG2 and BEL-7402 cell viability than that with singular local anesthetics or cisplatin treatment. Moreover, local anesthetics enhanced the cytotoxicity of cisplatin against HepG2 and BEL-7402 cells, accompanied by an increase in RASSF1A expression.

Conclusions: These data indicated that amide-type local anesthetics (lidocaine, ropivacaine and bupivacaine) have growth-inhibitory and demethylation effects in human hepatoma cells. We also found that these amide local anesthetics may enhance the cytotoxicity of cisplatin in human hepatocellular carcinoma cells possibly via upregulation of RASSF1A expression and demethylation.

Keywords: amide-type local anesthetics, DNA demethylation, cisplatin, RASSF1A, human hepatoma cells