Lidocaine triggered tumor cell apoptosis through the bitter taste receptor
US scientists found that lidocaine, a common local anesthetic, induces intracellular mobilization of calcium ions in head and neck carcinoma cells through activation of the bitter taste receptor T2R14. As reported in the journal Cell Reports, activation of T2R14 by lidocaine depolarizes mitochondria and induces apoptosis via the ubiquitin-proteasome protein degradation pathway.
Squamous cell carcinoma of the head and neck occurs on the mucosa of the oral cavity, nose, larynx, and pharynx as a result of exposure to carcinogens or human papillomavirus. About 900,000 new cases of cancer are reported each year, with a five-year mortality rate of about 50 percent. Oncologists treat these tumors with surgery, radiation therapy, chemotherapy, and sometimes immunotherapy. However, patients often suffer from side effects of existing treatments that reduce quality of life. In the long term, physical disfigurements, chronic pain, dependence on a tracheostomy or feeding tube, and inability to communicate verbally may occur.
Some studies suggest that lidocaine may also have antitumor effects and reduce the incidence of metastasis in some malignancies. However, it is unclear through which cellular effects lidocaine may exert antitumor effects.
Robert Lee's team at the University of Pennsylvania has suggested that lidocaine may have a pro-apoptotic effect on head and neck squamous cell cancer cells. The scientists thought that lidocaine might act through the bitter taste receptor T2R14. They found that lidocaine selectively activates the T2R14 receptor, which is widely present in oral tissues and other oropharyngeal regions. This activation leads to an increase in the intracellular concentration of calcium ions, and it increases independently of the blockade of potential-dependent sodium channels. It appeared that the calcium concentration increases due to the mobilization of intracellular stores, which are contained in the endoplasmic reticulum, through G-proteins.
Experiments then revealed that lidocaine rapidly depolarizes the mitochondrial membrane, which affects the overall viability of tumor cells. However, the final mechanism responsible for cancer cell apoptosis upon activation of the T2R14 receptor by lidocaine was recognized by the scientists as the accumulation of poly ubiquitinated proteins, which under normal calcium and reactive oxygen species concentrations should be degraded by proteasomes in the ubiquitin-proteasome pathway of protein degradation. However, this pathway fails to cope with a large number of such proteins, because of which the cell goes into apoptosis.
Researchers believe that lidocaine gels or intratumoral injections of lidocaine will make head and neck cancer treatment more effective, safer, and preserve quality of life. In addition, the researchers found that human papillomavirus-associated carcinoma cells express many times more of the T2R14 receptor, suggesting an even greater beneficial effect of lidocaine on these tumors.
Many factors can influence the risk of developing head and neck carcinomas. We recently told you that decreased diversity of the fungal community and overgrowth of several fungal organisms in the oral cavity are associated with a significantly increased risk of nasopharyngeal carcinoma.