Background: Substantial clinical and preclinical evidence have indicated the association between amide-linked\nlocal anesthesia and the long-term outcomes of cancer patients. However, the potential effects of local anesthesia\non cancer recurrence are inconclusive and the underlying mechanisms remain poorly understood.\nMethods: We systematically examined the effects of three commonly used local anesthetics in melanoma cells and\nanalyzed the underlying mechanisms focusing on small GTPases.\nResults: Ropivacaine and lidocaine but not bupivacaine inhibited migration and proliferation, and induced\napoptosis in melanoma cells. In addition, ropivacaine and lidocaine but not bupivacaine significantly augmented\nthe in vitro efficacy of vemurafenib (a B-Raf inhibitor for melanoma with BRAF V600E mutation) and dacarbazine (a\nchemotherapeutic drug). Mechanistically, ropivacaine but not bupivacaine decreased the activities of Ras\nsuperfamily members with the dominant inhibitory effects on RhoA and Ras, independent of sodium channel\nblockade. Rescue studies using constitutively active Ras and Rho activator calpeptin demonstrated that ropivacaine\ninhibited migration mainly through RhoA whereas growth and survival were mainly inhibited through Ras in\nmelanoma cells. We further detected a global reduction of downstream signaling of Ras and RhoA in ropivacainetreated\nmelanoma cells.\nConclusion: Our study is the first to demonstrate the anti-melanoma activity of ropivacaine and lidocaine but not\nbupivacaine, via targeting small GTPases. Our findings provide preclinical evidence on how amide-linked local\nanesthetics could affect melanoma patients.
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