Cytotoxicity of amide-linked local anesthetics on melanoma cells via inhibition of Ras and RhoA signaling independent of sodium channel blockade

Abstract

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

Nobiletin in Cancer Therapy: How This Plant Derived-Natural Compound Targets Various Oncogene and Onco-Suppressor Pathways

“…The abnormal expression of RhoA occurs in different cancers. It is said that the migration and survival of melanoma cells undergo inhibition via RhoA inhibition [226]. The great antitumor activity of lupeol depends on RhoA inhibition to suppress colon cancer capacity in proliferation and growth [227].…”

Anesthesia Medications and Interaction with Chemotherapeutic Agents

“…In melanoma cells, ropivacaine and lidocaine increased the in vitro efficacy of dacarbazine on the inhibition of migration, inhibition of proliferation, and increased apoptosis in melanoma cells. When either ropivacaine or lidocaine was used in the treatment of melanoma cells with vemurafenib, it was found to be more effective than vemurafenib alone in the treatment of melanoma [66]. Some studies have investigated the use of lidocaine for overcoming chemotherapeutic resistance in specific cancers.…”

Neurobiology of Cancer: Introduction of New Drugs in the Treatment and Prevention of Cancer

“…Therefore, these drugs might potentially reduce the stimulatory effect of nerves innervating melanoma. However, even though several papers have shown that local anesthetics might exert direct anti-cancer effects [ 140 , 141 , 142 ], there are no data in the available literature showing that local anesthetics can be used to suppress cancer via the attenuation of signal transmission between the nervous system and cancer tissue. Therefore, further research is necessary to assess whether blocking the transmission of action potentials via local anesthetic in axons innervating cancer tissue might affect cancer progression.…”