Lidocaine (Xylocaine®; Fresenius Kabi USA and other brands) which is often used as an anesthetic drug for outpatient medical procedures, also activates the bitter taste receptor 14 (T2R14) through two unique mechanisms that result in cancer cell death.[1]

This is the conclusion is based on a study by scientists from the Perelman School of Medicine at the University of Pennsylvania. Their research, supported by the National Institutes of Health, the Blavatnik Family Foundation, the American Head and Neck Society, and the McCabe Foundation and published in Cell Reports, [1] may pave the way for a clinical trial to test the addition of lidocaine to the standard of care therapy for patients with head and neck cancers.

The local anesthetic drug has long been suggested to have beneficial effects in cancer patients, but it wasn’t known how or why.

The preclinical study was led by Robert Lee, PhD, and Ryan Carey, MD, both assistant professors of Otorhinolaryngology – Head & Neck Surgery, and Zoey Miller, a Pharmacology graduate student at Penn and member of Lee’s lab.

The team found that lidocaine activates the bitter taste receptor T2R14, which is elevated in various cancer cells. When this receptor is activated, it starts a process called apoptosis, causing the cancer cells to die. The specific mechanisms that allow lidocaine to activate T2R14 are mitochondrial calcium ion overload (intracellular Ca2+), which depolarizes mitochondria and produces reactive oxygen species (ROS) that can damage biomolecules, and proteasome inhibition,* together resulting in cell death.

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Previous work [2] by the team showed that bitter taste receptors are found in many oral and throat cancer cells, where they trigger apoptosis, and that increased expression of these bitter receptors is correlated with improved survival outcomes in patients with head and neck cancer. In April 2023, a multi-institutional randomized clinical trial published in the Journal of Clinical Oncology found that breast cancer survival increased when lidocaine was administered before surgery. [3]

“We’ve been following this line of research for years but were surprised to find that lidocaine targets the one receptor that happened to be most highly expressed across cancers,” Lee said.

“T2R14 is found in cells throughout the body. What’s incredibly exciting is that a lot of existing drugs that activate it, so there could be additional opportunities to think about repurposing other drugs that could safely target this receptor,” he added.

Unclear function
While T2R14 helps the body perceive bitter taste in the mouth, the function of the receptor in other cells throughout the body is unclear. Lidocaine is typically injected into the skin or other tissues to prevent pain by blocking nerve signals and could easily be directly injected near or around accessible oral tumors.

“Speaking as a head and neck surgeon, we use lidocaine all the time,” Carey said.

“We know lidocaine is safe, we’re comfortable using it, and it’s readily available, which means it could be incorporated into other aspects of head and neck cancer care fairly seamlessly,” Carey further noted.

Elevated in HPV
The study, which was done primarily in cell lines of head and neck squamous cell carcinomas (HNSCCs), also found that T2R14 is particularly elevated in HNSCCs associated with the human papillomavirus (HPV), which is now the dominant form of HNSCC. As a result of these findings, Carey is planning to develop a clinical trial at Penn Medicine’s Abramson Cancer Center to test the addition of lidocaine to standard care for HPV-associated HNSCCs.

“While we’re not suggesting the lidocaine could cure cancer, we’re galvanized by the possibility that it could get an edge on head and neck cancer treatment and move the dial forward, in terms of improving treatment options for patients with this challenging form of cancer,” Carey concluded.

Note: * T2R14 activation with lidocaine depolarizes mitochondria, inhibits proliferation, and induces apoptosis. Concomitant with mitochondrial Ca2+ influx, ROS production causes T2R14-dependent accumulation of poly-ubiquitinated proteins, suggesting that proteasome inhibition contributes to T2R14-induced apoptosis.

[1] Miller ZA, Mueller A, Kim T, Jolivert JF, Ma RZ, Muthuswami S, Park A, McMahon DB, Nead KT, Carey RM, Lee RJ, Lidocaine induces apoptosis in head and neck squamous cell carcinoma through activation of bitter taste receptor T2R14. Cell Reports; November 22, 2023 DOI: 10.1016/j.celrep.2023.113437
[2] Carey RM, McMahon DB, Miller ZA, Kim T, Rajasekaran K, Gopallawa I, Newman JG, Basu D, Nead KT, White EA, Lee RJ. T2R bitter taste receptors regulate apoptosis and may be associated with survival in head and neck squamous cell carcinoma. Mol Oncol. 2022 Apr;16(7):1474-1492. doi: 10.1002/1878-0261.13131. Epub 2021 Dec 14. PMID: 34717036; PMCID: PMC8978516.
[3] Badwe RA, Parmar V, Nair N, Joshi S, Hawaldar R, Pawar S, Kadayaprath G, Borthakur BB, Rao Thammineedi S, Pandya S, Balasubramanian S, Chitale PV, Neve R, Harris C, Srivastava A, Siddique S, Vanmali VJ, Dewade A, Gaikwad V, Gupta S. Effect of Peritumoral Infiltration of Local Anesthetic Before Surgery on Survival in Early Breast Cancer. J Clin Oncol. 2023 Jun 20;41(18):3318-3328. doi: 10.1200/JCO.22.01966. Epub 2023 Apr 6. Erratum in: J Clin Oncol. 2023 Oct 20;41(30):4825. PMID: 37023374.

Featured image: Doctor discussing treatment options with a patient. Photo courtesy: © 2019 – 2023 Fotolia/Adobe. Used with permission.

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