局麻药可抑制人肝癌细胞的生长
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Local Anesthetics Inhibit the Growth of Human Hepatocellular Carcinoma Cells
背景与目的:肝细胞癌（HCC）是一种治疗手段有限的侵袭性癌症。回顾性研究表明术中应用局麻药（LAS）可以减少癌症复发。此外，实验研究也表明LAS具有抑制肿瘤细胞生长的作用。因此，本研究的目的便是探讨LAS对人肝癌细胞的影响。
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方法：在2个肝癌细胞株（HuH7 和 HepaRG）孵育48小时后，我们对2种局麻药（利多卡因和罗哌卡因）（10−2 ~ 10–6 M）的效应进行了研究。连同非监督全基因组表达谱分析和相关基因的实时定量聚合酶链反应一道我们进行了细胞存活率、细胞周期分析、细胞凋亡和衰老试验。
结果：我们发现LAS浓度依赖性降低了HuH7细胞株的生存能力和增殖能力（罗哌卡因：从5 ×10−3 M 时的92% [P < .001] 到 10−4 M 时的40% [P = .02] ；利多卡因： 从87% [P < .001] 到 37% [P = .02])。而对HepaRG细胞株生存能力和增殖能力而言，从利多卡因5 ×10−3 M 时的58% [P < .001] 到 10−4 M时的 29% [P = .04] ，5 × 10−3 M罗哌卡因时其生存能力和增殖能力为59% [P < .001]。LAS对分化好的HepaRG细胞无影响。罗哌卡因降低关键细胞周期调控因子即细胞周期蛋白A2（cyclin A2）、细胞周期蛋白B1（cyclin B1）、细胞周期蛋白B2（cyclin B2）和细胞周期蛋白依赖性激酶1的mRNA水平及核内细胞增殖标记物MKI67的表达。利多卡因对细胞周期无明显影响但却使腺瘤性结肠息肉病mRNA水平增加了10倍（P < .01），其在这一过程中扮演了Wnt /β-catenin通路的拮抗剂的角色。两种LAS均增加Huh7和HepaRG祖细胞的凋亡(P < .01)。
结论：数据表明，LAS引起了肿瘤细胞的基因谱深刻的变化，包括引起细胞生长抑制和诱导凋亡作用的调节细胞周期相关基因的表达。
Le Gac G1, Angenard G, Clément ，Local Anesthetics Inhibit the Growth of Human Hepatocellular Carcinoma Cells， Anesth Analg. Nov 2017 ;125(5):1600-1609. doi: 10.1213/ANE.0000000000002429.
Background: Hepatocellular carcinoma (HCC) is an aggressive cancer with limited therapeutic options. Retrospective studies have shown that the administration of local anesthetics (LAs) during cancer surgery could reduce cancer recurrence. Besides, experimental studies reported that LAs could inhibit the growth of cancer cells. Thus, the purpose of this study was to investigate the effects of LAs on human HCC cells.
Methods: The effects of 2 LAs (lidocaine and ropivacaine) (10−2 to 10–6 M) were studied after an incubation of 48 hours on 2 HCC cell lines, namely HuH7 and HepaRG. Cell viability, cell cycle analysis, and apoptosis and senescence tests were performed together with unsupervised genome-wide expression profiling and quantitative real-time polymerase chain reaction for relevant genes.
Results:We showed that LAs decreased viability and proliferation of HuH7 cells (from 92% [P < .001] at 5 × 10−3 M to 40% [P = .02] at 10−4 M with ropivacaine and from 87% [P < .001] to 37% [P = .02] with lidocaine) and HepaRG progenitor cells (from 58% at 5 × 10−3 M [P < .001] to 29% at 10−4 M [P = .04] with lidocaine and 59% [P < .001] with ropivacaine 5 × 10−3 M) in concentration-dependent manner. LAs have no effect on well-differentiated HepaRG. Ropivacaine decreased the mRNA level of key cell cycle regulators, namely cyclin A2, cyclin B1, cyclin B2, and cyclin-dependent kinase 1, and the expression of the nuclear marker of cell proliferation MKI67. Lidocaine had no specific effect on cell cycle but increased by 10× the mRNA level of adenomatous polyposis coli (P < .01), which acts as an antagonist of the Wnt/β-catenin pathway. Both LAs increased apoptosis in Huh7 and HepaRG progenitor cells (P < .01).
Conclusion:The data demonstrate that LAs induced profound modifications in gene expression profiles of tumor cells, including modulations in the expression of cell cycle–related genes that result in a cytostatic effect and induction of apoptosis.
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