Effect of Lidocaine on Breast Cancer

Breast cancer is one of the most commonly diagnosed cancers and the second leading cause of cancer-related death in women. [1] As surgical resection is the primary method of treatment for these patients, there is a high risk of blood-borne metastasis. This occurs when trauma to the central tumor causes tumor cells to shed and enter the bloodstream, circulating and then exiting into distant regions of the body. [2] Additionally, surgical operations have been shown to decrease natural killer cell function and T cell response for one to four weeks after surgery. These immunosuppressive effects put cancer patients in the postoperative state at a higher risk of developing metastases. As a result, there is significant interest in potential modifications to breast cancer surgery that decrease the risk of negatively affecting a patient’s cancer status with minimal side effects. One area of interest is the effect of lidocaine on breast cancer cells.

Several retrospective studies have suggested regional anesthesia may have a positive effect on cancer relapse and recurrence. Regional anesthesia is administered by injecting local anesthetic at a target location to temporarily disrupt pain signals from a specific region of the body. Potential benefits include reducing surgical stress from neuroendocrine and immunological disturbances, reducing the use of systemic anesthesia and opiates (which have been shown to hinder cell immunity), as well as having a direct inhibitory effect on cancer cells. [1]

In an in vitro experiment, three human breast cancer cell lines were isolated and grown in culture plates. These breast cancer cells were treated with increasing doses of lidocaine, an anesthetic that is commonly used for regional anesthesia. Lidocaine significantly reduced cell viability in all three cell lines, as measured by the MTT colorimetric assay. The anesthetic was also shown to inhibit cell migration, as exposed cells demonstrated reduced wound closure compared to control cells. The same researchers then conducted an in vivo experiment in mice to further assess the effects of lidocaine on human breast cancer cells. Cancer cells were injected intraperitoneally, and the global tumor volume was measured. Mice injected with lidocaine exhibited prolonged survival times and developed significantly smaller tumors than control mice. [3] At the conclusion of these molecular and preclinical experiments, these researchers suggest lidocaine may have a protective effect against human breast cancer cells.

Lidocaine is an amide anesthetic routinely administered for topical or surface anesthesia, and is injected into the subarachnoid and epidural spaces to block sensory and motor neural transmission. [4] Cytotoxicity assays performed on natural killer (NK) cells demonstrated that clinically relevant concentrations of lidocaine increases performance of NK cells, which are a crucial pillar of the immune response. [4,5] One in vitro study on human hepatocellular carcinoma cells found cancer cells treated with lidocaine exhibited a decrease in Bcl-2 levels with a concurrent increase in Bax concentrations. These two molecules are part of the Bcl-2 family, a group of regulatory proteins modulating cell death, composed of inhibitors (Bcl-2) and promoters (Bax). It was further observed that treated cultures with cancer cells exhibited a significant increase in caspase-3, a “death protease” catalyzing the cleavage of many key cellular proteins. [6] Matrix-metalloproteinase 9 (MMP-9) is a proteolytic enzyme which plays a crucial role in tumor metastasis by regulating pathological remodeling processes involving inflammation and fibrosis. [7] Another in vitro study demonstrated lidocaine can significantly decrease the secretion of MMP-9 by repressing the activity of tumor necrosis factor ɑ (TNF-ɑ), a proinflammatory cytokine. [8]

The cancer microenvironment is extraordinarily complex, involving many molecular cascades and organ systems. Although lidocaine has been shown to have a protective effect against human breast cancer cells, the extant literature has thus far been restricted to artificial and preclinical experimentation. As such, further clinical research is needed to determine lidocaine’s true benefit. What’s more, there is a lack of research on the specific mechanisms by which lidocaine takes effect on cancer cells. Investigating these can help explain the beneficial properties of lidocaine in cancer progression.

References

1. Li, Ru, et al. “Effects of Local Anesthetics on Breast Cancer Cell Viability and Migration.” BMC Cancer, vol. 18, no. 1, June 2018, p. 666. BioMed Central, https://doi.org/10.1186/s12885-018-4576-2

2. Choy, A., and P. McCulloch. “Induction of Tumour Cell Shedding into Effluent Venous Blood Breast Cancer Surgery.” British Journal of Cancer, vol. 73, no. 1, Jan. 1996, pp. 79–82. www.nature.com, https://doi.org/10.1038/bjc.1996.14

3. Chamaraux-Tran, Thiên-Nga, et al. “Antitumor Effects of Lidocaine on Human Breast Cancer Cells: An In Vitro and In Vivo Experimental Trial.” Anticancer Research, vol. 38, no. 1, Jan. 2018, pp. 95–105. ar.iiarjournals.org, https://ar.iiarjournals.org/content/38/1/95

4. Zhang, Caihui, et al. “Local Anesthetic Lidocaine and Cancer: Insight Into Tumor Progression and Recurrence.” Frontiers in Oncology, vol. 11, 2021. Frontiers, https://www.frontiersin.org/articles/10.3389/fonc.2021.669746

5. Ramirez, Maria F., et al. “The Effect of Clinically Therapeutic Plasma Concentrations of Lidocaine on Natural Killer Cell Cytotoxicity.” Regional Anesthesia & Pain Medicine, vol. 40, no. 1, Jan. 2015, pp. 43–48. rapm.bmj.com, https://doi.org/10.1097/AAP.0000000000000191

6. Xing, Wei, et al. “Lidocaine Induces Apoptosis and Suppresses Tumor Growth in Human Hepatocellular Carcinoma Cells In Vitro and in a Xenograft Model In Vivo.” Anesthesiology, vol. 126, no. 5, May 2017, pp. 868–81. DOI.org (Crossref), https://doi.org/10.1097/ALN.0000000000001528

7. Yabluchanskiy, Andriy, et al. “Matrix Metalloproteinase-9: Many Shades of Function in Cardiovascular Disease.” Physiology, vol. 28, no. 6, Nov. 2013, pp. 391–403. PubMed Central, https://doi.org/10.1152/physiol.00029.2013

8. Piegeler, T., et al. “Clinically Relevant Concentrations of Lidocaine and Ropivacaine Inhibit TNFα-Induced Invasion of Lung Adenocarcinoma Cells in Vitro by Blocking the Activation of Akt and Focal Adhesion Kinase.” British Journal of Anaesthesia, vol. 115, no. 5, Nov. 2015, pp. 784–91. DOI.org (Crossref), https://doi.org/10.1093/bja/aev341