Amide-type local anesthetics may suppress tumor cell proliferation and sensitize Human Hepatocellular Carcinoma Cells to Cisplatin via upregulation of RASSF1A expression and demethylation.
Amide-type local anesthetics may suppress tumor cell proliferation and sensitize Human Hepatocellular Carcinoma Cells to Cisplatin via upregulation of RASSF1A expression and demethylation.
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酰胺类局麻药可能通过上调 RASSF1A 表达和去甲基化来抑制肿瘤细胞增殖并使人肝细胞癌细胞对顺铂敏感
DOI：
10.7150/jca.46630
复制
发表时间：
2020
影响因子：
3.9
通讯作者：
Xing W
中科院分区：
文献类型：
--
作者：
Chen D;Yan Y;Xie J;Pan J;Chen Y;Li Q;Yuan Y;Zeng W;Xing W
背景：已有研究表明，局部麻醉药对多种类型的细胞具有毒性。此外，几种局部麻醉剂已被证实发挥去甲基化作用并调节人类癌细胞的增殖。我们的前期研究结果表明，利多卡因可能发挥潜在的抗肿瘤活性，并在体外和体内增加顺铂对肝癌的敏感性。最近的一项研究表明，利多卡因通过上调肿瘤抑制基因（TSG）去甲基化的启动子RASSF 1A来使乳腺癌细胞对顺铂敏感。我们试图确定酰胺型局麻药（利多卡因，罗哌卡因和布比卡因）是否对人肝癌细胞产生生长抑制作用，并确定酰胺型局麻药是否通过上调RASSF 1A表达使人肝癌细胞对顺铂介导的细胞毒性敏感。方法：人肝癌细胞株HepG 2和BEL-7402分别与利多卡因、罗哌卡因和布比卡因共同孵育。研究了有或没有顺铂的局部麻醉处理的细胞的活力。此外，我们评估了用三种局部麻醉剂处理HepG 2和BEL-7402细胞后RASSF 1A的表达，并确定了RASSF 1A表达对顺铂对这些细胞的毒性的影响。结果如下：酰胺类局麻药（利多卡因、罗哌卡因和布比卡因）处理后，HepG 2和BEL-7402细胞的存活率显著降低。在这些细胞中，顺铂和局部麻醉剂的联合治疗表现出更强的活力降低。利多卡因、罗哌卡因和布比卡因促进RASSF 1A表达的显著增加和RASSF 1A甲基化的降低。与单独使用局麻药或顺铂治疗相比，局麻药和顺铂联合治疗导致HepG 2和BEL-7402细胞活力水平显著降低。此外，局部麻醉剂增强顺铂对HepG 2和BEL-7402细胞的细胞毒性，伴随着RASSF 1A表达的增加。结论：这些数据表明，酰胺类局麻药（利多卡因，罗哌卡因和布比卡因）在人肝癌细胞中具有生长抑制和去甲基化作用。我们还发现这些酰胺类局麻药可能通过上调RASSF 1A表达和去甲基化来增强顺铂对人肝癌细胞的细胞毒性。
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.
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DOI：
10.1158/1940-6207.capr-13-0067
发表时间：
2013-04
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
--
作者：
Schneider BG;Peek RM Jr
通讯作者：
Peek RM Jr
影响因子：
5.7
作者：
Sakaguchi, M;Kuroda, Y;Hirose, M
通讯作者：
Hirose, M
影响因子：
15.9
作者：
Levesley, Jane;Lusher, Meryl E.;Coyle, Beth
通讯作者：
Coyle, Beth
影响因子：
7.5
作者：
Liu, Juan;Xie, Yi-Shan;Luo, He-Sheng
通讯作者：
Luo, He-Sheng
影响因子：
30.8
作者：
Costello, JF;Fr端hwald, MC;Plass, C
通讯作者：
Plass, C