Alabama Anesthesia Professionals

Lidocaine in Cancer Progression

Local anesthetics have played a transformative role in modern medicine, enabling safe and efficient surgical procedures. Lidocaine, a local agent which was first introduced in 1943 by two Swedish chemists, remains one of the most widely used anesthetics due to its rapid onset, intermediate duration of action, and favorable safety profile. Its primary mechanism of action involves the reversible blockade of voltage-gated sodium channels, which then inhibits neuronal depolarization and interrupts nociceptive signaling. Beyond its established analgesic role, lidocaine has been shown to exert direct and indirect anti-tumor effects. Clinically, retrospective and prospective studies have reported associations between perioperative lidocaine administration and positive impacts on cancer progression, including reduced recurrence and enhanced survival in certain cancer types. These findings highlight lidocaine as a potential adjuvant in cancer care, warranting further exploration into its mechanistic underpinnings and therapeutic implications.

Lidocaine is an amide-type local anesthetic with a shorter duration of action than similar agents (e.g., ropivacaine, levobupivacaine), but it offers a wide safety margin and minimal toxicity.1 Its primary mechanism of action is the reversible blockade of voltage-gated sodium channels (VGSCs), which play an important role in neuropathic and inflammatory nociception. Lidocaine’s inhibition of the NaV1.8 sodium channel subtype, which is especially sensitive to the drug, plays a key role in its analgesic efficacy. While lidocaine primarily inhibits VGSCs, it also interacts with multiple ion channels, including potassium, calcium, transient receptor potential (TRP), and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels.2 Lidocaine also modulates other ionotropic receptors, including the glutamate receptors (i.e., NMDA, glycine, serotonin), acetylcholine receptors (i.e., muscarinic, nicotinic), and G-protein coupled receptors (GPCRs). These diverse molecular targets are indicative of the agent’s broader pharmacological actions, including anti-arrhythmic, analgesic, and anti-inflammatory effects.3

 Lidocaine’s anti-tumor effects have been linked to its actions on multiple molecular targets. One major pathway involves the inhibition of voltage-gated sodium channels (VGSCs), which reduces excitability and blocks nociception.4 The NaV1.5 subunit is a VGSC isoform that normally contributes to cardiovascular health; however, cancer cells will aberrantly express the neonatal splice variant of NaV1.5, which promotes persistent sodium influx. The excess sodium alters intracellular ion balance and signaling in ways that favor cancer proliferation, invasion, and metastasis. By blocking the NaV1.5 variant, lidocaine may help slow cancer progression.

The Transient Receptor Potential Melastatin 7 is part of the TRP channel family and allows for the passage of divalent cations, such as Mg2+, Ca2+, and Zn2+. TRPM7 activation is linked with phenotypes such as cancer cell growth, motility, and invasion, particularly in glioma cells.5 In several clinical studies, lidocaine has been shown to block TRPM7, which significantly inhibits the growth, viability, and migration of both glioma and breast cancer cells.5,6

Another relevant TRP channel is the Transient Receptor Potential Vanilloid 1(TRPV1), which is predominantly expressed in trigeminal ganglion neurons, particularly in the dorsal root ganglion (DRG). TRPV1 plays a distinct role in inhibiting gastric cancer development through a calcium signaling pathway. Indeed, reduced levels of TRPV1 has been associated with poorer survival outcomes in patients with gastric cancer.7 Lidocaine activates the TRPV1 gene, elevating intracellular calcium ion concentrations and driving apoptosis in glioma cell lines. Additionally, lidocaine activates protein kinase CaMKII, which phosphorylates TRPV1 ion channels, resulting in a calcium overload for glioblastoma cells and their subsequent pyroptosis.8

Lidocaine remains a cornerstone anesthetic in clinical practice, and growing evidence suggests its therapeutic potential extends beyond analgesia. Through the inhibition of aberrantly expressed sodium channel variants and modulation of TRP channels, lidocaine demonstrates promising anti-tumor activity, including the suppression of proliferation, invasion, and metastasis, as well as the induction of apoptosis and pyroptosis. While these findings highlight lidocaine as a potential adjuvant in oncologic care, further mechanistic studies and large-scale clinical trials are needed to clarify its role and optimize its application.

References

  1. Taylor A., McLeod G., Basic Pharmacology of Local Anaesthetics. BJA Education. 2020;20(2)., 34-41. https://doi.org/10.1016/j.bjae.2019.10.002
  2. Nakahira K., Oshita K., Itoh M., Takano M., Sakaguchi Y., Ishihara K., Clinical Concentrations of Local Anesthetics Bupivacaine and Lidocaine Differentially Inhibit Human Kir2.x Inward Rectifier K+ Channels. Anesthesia & Analgesia. 2016;122(4):1038-1047. https://doi.org/10.1213/ane.0000000000001137
  3. Flondor M., Listle H., Kemming G.I., Zwissler B., Hofstetter C., Effect of Inhaled and Intravenous Lidocaine on Inflammatory Reaction in Endotoxaemic Rats. European Journal of Anaesthesiology. 2009;27(1):53-60. https://doi.org/10.1097/eja.0b013e32832b8a70
  4. Brackenbury W.J., Palmieri C., Blocking Channels to Metastasis: Targeting Sodium Transport in Breast Cancer. Breast Cancer Research. 2023;25(1). https://doi.org/10.1186/s13058-023-01741-1
  5. Leng T., Li M., Shen J., et al. Suppression of TRPM7 Inhibits Proliferation, Migration, and Invasion of Malignant Human Glioma Cells. CNS Neuroscience & Therapeutics. 2014;21(3):252-261. https://doi.org/10.1111/cns.12354
  6. Liu H., Dilger J.P., Lin J., Lidocaine Suppresses Viability and Migration of Human Breast Cancer Cells: TRPM7 as a Target for Some Breast Cancer Cell Lines. Cancers. 2021;13(2):234-234. https://doi.org/10.3390/cancers13020234
  7. Gao N., Yang F., Chen S., Wan H., Zhao X., Dong H., The Role of TRPV1 Ion Channels in the Suppression of Gastric Cancer Development. Journal of Experimental & Clinical Cancer Research. 2020;39(1). https://doi.org/10.1186/s13046-020-01707-7
  8. Zhou B., Lin Y., Chen S., et al. Activation of Ca2+/Calmodulin-Dependent Protein Kinase II (CaMKII) with Lidocaine Provokes Pyroptosis of Glioblastoma Cells. Bulletin of Experimental Biology and Medicine. 2021;171(3):297-304. https://doi.org/10.1007/s10517-021-05216-1