Mechanisms of Action by Which Local Anesthetics Reduce Cancer Recurrence: A Systematic Review

Abstract

Background Surgery in concert with anesthesia is a key part of the management of advanced-stage cancers. Anesthetic agents such as opioids and volatile anesthetics have been shown to promote recurrence in preclinical models, whereas some animal models have shown that the use of lidocaine may be beneficial in reducing cancer recurrence. The purpose of this article is to review the current literature to highlight the mechanisms of action by which local anesthetics are thought to reduce cancer recurrence. Methods A systematic review was conducted using the PubMed (1966 to 2018) electronic database. Search terms included “lidocaine,” “ropivicaine,” “procaine,” “bupivicaine,” “mepivicaine,” “metastasis,” “cancer recurrence,” “angiogenesis,” and “local anesthetics” in various combinations. The search yielded 146 total abstracts for initial review, 20 of which met criteria for inclusion. Theories for lidocaine’s effect on cancer recurrence were recorded. All studies were reviewed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. Results Numerous mechanisms were proposed based on the local anesthetic used and the type of cancer. Mechanisms include those that are centered on endothelial growth factor receptor, voltage-gated sodium and calcium channels, transient receptor melanoplastin 7, hyperthermia, cell cycle, and demyelination. Conclusions In vivo models suggest that local anesthetic administration leads to reduced cancer recurrence. The etiology of this effect is likely multifactorial through both inhibition of certain pathways and direct induction of apoptosis, a decrease in tumor migration, and an association with cell cycle–mediated and DNA-mediated effects. Additional research is required to further define the clinical implications.

In Vivo Evidence for Voltage-Gated Sodium Channel Expression in Carcinomas and Potentiation of Metastasis

“…The combined in vitro and in vivo preclinical evidence suggest that repurposing VGSC-inhibiting medication to the oncology setting may have therapeutic value. Given that such drugs are in widespread clinical use for other indications, several observational studies have investigated potential associations with cancer outcomes [100,101,102]. For example, it has been shown that the risk of recurrence in patients with BCa or PCa who received general anaesthesia and perioperative lidocaine was reduced compared to those who did not receive lidocaine [103,104].…”

Repositioning Lidocaine as an Anticancer Drug: The Role Beyond Anesthesia

“…As it has been shown that through different mechanisms, such as sodium channel inhibitor and the regulation of G protein-coupled receptors, lidocaine exerts its multifunctional effects in anti-inflammation ( Caracas et al, 2009 ; Cruz et al, 2017 ), analgesia and antihyperalgesia ( Tian et al, 2009 ), immuno-modulation ( Kim et al, 2017 ), anti-arrhythmia ( Harrison and Collinsworth, 1974 ), and as an antibacterial ( Begec et al, 2007 ). Importantly, as the focus of current review, growing evidence suggests that local anesthetics may also provide benefits in the treatment of cancer by inhibiting proliferation, invasion, and migration of certain cancer cells ( Grandhi and Perona, 2019 ). Literatures show that lidocaine is not only able to kill various types of cancer cells, but has also been reported to sensitize various chemotherapeutics to many types of resistant cancer cells.…”

Anaesthesia and cancer: can anaesthetic drugs modify gene expression?

“…Src is also involved with regulation of the cytoskeletal changes required for cell migration by phosphorylation of the proteins involved in focal adhesions and actin binding [ 95 ]. Lidocaine and ropivacaine have been reported to decrease cancer cell migration by inhibiting Src activation induced by tumour necrosis factor-α and phosphorylation of intercellular adhesion molecule-1 [ 96 ]. A later study showed that these local anaesthetics may have an anti-inflammatory effect, since in endothelial cells they effectively block inflammatory signaling of TNFα by attenuating the recruitment of p85 in the TNF-1 receptor.…”