From anesthetic to anticancer agent: Rethinking lidocaine in breast oncology
Key Highlights
- Lidocaine, an established local anesthetic, has demonstrated potential to reduce breast cancer recurrence and improve survival rates in recent clinical studies.
- It exerts anticancer effects by blocking sodium channels, inducing apoptosis, reversing DNA methylation, and inhibiting tumor growth and metastasis pathways.
- Lidocaine also modulates the immune system, reducing inflammation and enhancing natural killer cell activity during the perioperative period.
- The drug activates stress-sensing receptors like T2R14 in cancer cells, leading to rapid cell death through internal stress signals.
- As a low-cost, widely available medication with minimal systemic toxicity, lidocaine could be integrated into multimodal breast cancer treatment strategies pending further research.
Drug repositioning refers to taking an existing, approved drug and identifying new therapeutic uses for it. I was recently listening to an interview with Dr. David Fajgenbaum, author of Chasing My Cure and cofounder of Every Cure, an organization dedicated to systematically mapping and repurposing existing medicines for diseases they were not originally designed to treat.
His personal story is extraordinary, and the science and strategy behind his work are equally compelling. Fajgenbaum pointed out the striking findings of a 2023 breast cancer study in India, where lidocaine injections before surgery led to a significant reduction in cancer recurrence and mortality.1 The study of ∼1,600 was a prospective randomized control trial that showed a 30% improvement in survival, achieved with a simple, off-patent drug.
Lidocaine is a strong example of a mature, widely used drug with untapped potential. It was discovered in 1943, the patent was granted in 1948 under the trade name Xylocaine, and it appears on the World Health Organization’s List of Essential Medicines.
In dentistry, we rely on it routinely for local anesthesia through blocks or infiltrations, and beyond dentistry it’s used for: topical anesthesia during endoscopy and intubation; transdermally to treat neuropathic pain; intravenously for certain ventricular arrhythmias; and in select cases for neonatal seizures. Given this broad clinical footprint, researchers have started examining how lidocaine’s actions extend beyond anesthesia and into cancer biology.
Mechanisms of action for breast cancer
Lidocaine appears to exert anticancer effects through many complementary biological pathways, both direct (acting on cancer cells/tissues) and indirect (modulating the surgical or tumor microenvironment).
Sodium channel blockade
Breast cancer cells express voltage-gated sodium channels that promote invasion and metastatic behavior. Lidocaine’s core pharmacologic action blocks these channels, disrupting prometastatic signaling, especially during tumor manipulation in surgery.2
Direct induction of apoptosis
Lidocaine can push breast cancer cells toward programmed cell death by disrupting their energy centers (the mitochondria). When this happens, the cell releases internal “danger signals” that turn on caspases, the enzymes that carry out cell death. At the same time, the proteins that help cancer cells survive are reduced, while proteins that promote healthy cell turnover increase. Together, these shifts make the cancer cell much more likely to stop functioning and die.3,4
Epigenetic demethylation
At clinically relevant concentrations, lidocaine partially reverses abnormal DNA methylation.5 This reactivates silenced tumor-suppressor genes and increases cancer cell sensitivity to chemotherapy.
Suppression of growth and survival pathways
Lidocaine turns down several of the “growth switches” that cancer cells rely on. These pathways normally tell a cancer cell to keep dividing, repairing itself, and resisting treatment. When lidocaine dampens those signals, the cells slow their growth, stop progressing through the cell cycle, and become more vulnerable. It can also influence small regulatory molecules that control growth receptors like epidermal growth factor receptor (EGFR), further reducing the cancer cell’s ability to multiply.6
Blocking invasion and metastasis
Lidocaine makes it harder for cancer cells to move, invade nearby tissue, and spread. It blocks the signals that help cancer cells loosen, change shape, break down surrounding tissue, and migrate. By interrupting these steps, lidocaine slows local invasion and reduces the chance of metastatic spread.7
Anti-inflammatory and immune-modulating effects
Surgery triggers a surge of inflammation and stress signals that can unintentionally promote metastasis. Lidocaine helps counter this effect by reducing perioperative cytokine spikes and dampening the body’s stress response. At the same time, it strengthens antitumor immunity.
Lidocaine enhances natural killer (NK) cell activity and shifts tumor-associated macrophages away from the M2, tumor-supporting state toward the M1 phenotype that actively fights cancer. Together, these immune-modulating actions create a less favorable environment for cancer spread during the vulnerable perioperative window.5
Antiangiogenic effects
Lidocaine decreases vascular endothelial growth factor (VEGF ) signaling and endothelial adhesion molecule expression, reducing new blood vessel formation, and limiting opportunities for tumor cells to escape into circulation.5,8
Bitter-taste receptor activation
A newly identified pathway shows that lidocaine activates T2R14, a “bitter taste” receptor that is abnormally expressed inside many types of cancer cells. Although known for detecting bitter compounds on the tongue, these receptors also appear in tumor cells, where they act as stress-sensing proteins. When lidocaine turns on T2R14, it triggers a cascade of internal stress signals that overwhelm the cancer cell’s mitochondria and shut down its proteasome, leading to rapid cancer-cell death.9
Lidocaine shows potential to bolster many standard treatments: it can be seamlessly integrated into surgical protocols (the most immediate use case), might improve the effectiveness of chemotherapies (by sensitizing cancer cells), and could positively influence the tumor immune environment alongside emerging therapies.
One of lidocaine’s advantages is that it does not have known cross-toxicities with other treatments when used in its usual dosing range—it’s largely out of the system within hours, and when used locally, systemic exposure is low.10
Ongoing research is needed to translate these promising laboratory findings into full clinical combination strategies, but early data suggest lidocaine could become a valuable adjunct in multimodal breast cancer therapy. Because companies won’t profit from a generic drug like lidocaine, advancing this work will rely on researchers, cooperative groups, and public funding to support the trials needed to bring this low-cost option into broader clinical practice.
References
1. Badwe RA, Parmar V, Nair N, et al. Effect of peritumoral infiltration of local anesthetic before surgery on survival in early breast cancer. J Clin Oncol. 2023;41(18):3318-3328. doi:10.1200/JCO.22.01966
2. Luo Q, Wu T, Wu W, et al. The functional role of voltage-gated sodium channel nav1.5 in metastatic breast cancer. Front Pharmacol. 2020;11:1111. doi:10.3389/fphar.2020.01111
3. Han BS, Jung KH, Lee JE, et al. Lidocaine enhances the efficacy of palbociclib in triple-negative breast cancer. Am J Cancer Res. 2022;12(7):3083-3098.
4. Long D, Fang X, Yuan P, Cheng L, Li H, Qu L. Lidocaine promotes apoptosis in breast cancer cells by affecting VDAC1 expression. BMC Anesthesiol. 2022;22(1):273. doi:10.1186/s12871-022-01818-y
5. Zhang C, Xie C, Lu Y. Local anesthetic lidocaine and cancer: insight into tumor progression and recurrence. Front Oncol. 2021;11:669746. doi:10.3389/fonc.2021.669746
6. Wu Chuang A, Kepp O, Kroemer G, Bezu L. Direct cytotoxic and indirect, immune-mediated effects of local anesthetics against cancer. Front Oncol. 2022;11:821785. doi:10.3389/fonc.2021.821785
7. Seok Han B, Ko S, Seok Park M, et al. Lidocaine combined with general anesthetics impedes metastasis of breast cancer cells via inhibition of TGF-β/Smad-mediated EMT signaling by reprogramming tumor-associated macrophages. Int Immunopharmacol. 2024;142(Pt B):113207. doi:10.1016/j.intimp.2024.113207
8. Gao J, Hu H, Wang X. Clinically relevant concentrations of lidocaine inhibit tumor angiogenesis through suppressing VEGF/VEGFR2 signaling. Cancer Chemother Pharmacol. 2019;83(6):1007-1015. doi:10.1007/s00280-019-03815-4
9. Miller ZA, Mueller A, Kim T, et al. Lidocaine induces apoptosis in head and neck squamous cell carcinoma through activation of bitter taste receptor T2R14. Cell Rep. 2023;42(12):113437. doi:10.1016/j.celrep.2023.113437
10. Beecham GB, Nessel TA, Goyal A. Lidocaine. StatPearls. Treasure Island Publishing; August 16, 2024.
About the Author
Anne O. Rice, BS, RDH, CDP, FAAOSH
Anne O. Rice, BS, RDH, CDP, FAAOSH, founded Oral Systemic Seminars after over 35 years of clinical practice and is passionate about educating the community on modifiable risk factors for dementia and their relationship to dentistry. She is a certified dementia practitioner, a longevity specialist, a fellow with AAOSH, and has consulted for Weill Cornell Alzheimer’s Prevention Clinic, FAU, and Atria Institute. Reach out to Anne at anneorice.com.