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Local Anesthetics Inhibit the Growth of Human Hepatocellular Carcinoma Cells

Le Gac, Grégoire MD*†; Angenard, Gaëlle BS*; Clément, Bruno PhD*; Laviolle, Bruno MD, PhD; Coulouarn, Cédric PhD*; Beloeil, Hélène MD, PhD*†

doi: 10.1213/ANE.0000000000002429
Cancer and Supportive Care: Original Laboratory Research Report

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) (102 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 104 M with ropivacaine and from 87% [P < .001] to 37% [P = .02] with lidocaine) and HepaRG progenitor cells (from 58% at 5 × 103 M [P < .001] to 29% at 104 M [P = .04] with lidocaine and 59% [P < .001] with ropivacaine 5 × 103 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).

CONCLUSIONS: 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.

Supplemental Digital Content is available in the text.Published ahead of print August 29, 2017.

From the *INSERM, UMR 991, and Université de Rennes 1, Rennes, France; CHU Rennes, Pôle Anesthésie et Réanimation, Inserm CIC 1414, Rennes, France; and CHU Rennes, Clinical Pharmacology Department and Inserm CIC 1414, Université de Rennes 1, Rennes, France.

Accepted for publication July 25, 2017.

Published ahead of print August 29, 2017.

Funding: This research was supported by INSERM, University of Rennes 1, Ligue Contre le Cancer InCa/Canceropole and SFAR (French society of Anesthesia and Intensive Care) France.

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

Reprints will not be available from the authors.

Address correspondence to Hélène Beloeil, MD, PhD, Pôle d’Anesthésie Réanimation Chirurgicale, CHU Rennes, 2 Rue Henri Le Guilloux, 35033 Rennes Cedex 9, France. Address e-mail to helene.beloeil@chu-rennes.fr.

© 2017 International Anesthesia Research Society
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