A new study reveals how the common local anesthetic lidocaine activates bitter taste receptors to exert anti-cancer effects on head and neck cancers. Because the drug is low-cost and readily available, it could easily be used to treat patients with this challenging cancer.
Anyone who has had a wound sutured or had a dental procedure such as filling a tooth may be familiar with lidocaine. It's known how this local anesthetic drug works to relieve pain, but it's also thought lidocaine may have benefits for cancer patients, although it's not entirely clear how.
Now, a study led by researchers at the University of Pennsylvania School of Medicine has solved the long-standing mystery of how lidocaine causes the death of certain cancer cells.
"We had been looking at this line of research for years and were surprised to find that lidocaine targets a receptor that happens to be highly expressed in a variety of cancers," said Robert Lee, the study's corresponding author.
This 'receptor' is T2R14, a bitter taste receptor expressed in head and neck squamous cell carcinoma (HNSCC), a cancer with high mortality and treatment-related morbidity. HNSCC develops in the oral and nasal mucosa due to exposure to environmental carcinogens and/or human papilloma virus (HPV).
In addition to their role in bitter taste perception, bitter taste receptors (T2Rs) are also involved in innate immunity, thyroid function, cardiac physiology, and other biological processes. Researchers have studied T2Rs in ovarian cancer, breast cancer and HNSCC, with T2R14 being the most studied.
Researchers have previously found that T2Rs are present in many oral and throat cancers and trigger apoptosis, or programmed cell death, and that increased expression of T2Rs is associated with improved survival in HNSCC patients. A study published earlier this year found that breast cancer patients had improved survival rates if lidocaine was injected around their tumors before surgery.
"T2R14 is found in cells throughout the body. Incredibly, many existing drugs can activate it, so there may be more opportunities to consider redesigning other drugs to safely target this receptor."
Using HNSCCs cell lines, researchers found that lidocaine can activate the T2R14 receptor and cause cancer cell apoptosis. Specifically, activation of the drug causes mitochondrial calcium overload, depolarizes mitochondrial membranes, and significantly reduces HNSCC cell viability. It also leads to the production of reactive oxygen species (ROS), further indicating mitochondrial dysfunction and cellular stress.
Research data also indicate that lidocaine inhibits proteasomal degradation. Proteasomes remove thousands of short-lived, damaged, misfolded or obsolete proteins from cells. When the activity of the proteasome is inhibited, proteins that need to be degraded accumulate, thereby inducing apoptosis. Lidocaine-induced proteasome inhibition was reversed when ROS generation or T2R14 signaling was inhibited, suggesting that proteasome inhibition results from T2R stimulation, downstream mitochondrial dysfunction, and ROS.
It can be said that one advantage of HNSCC is the easy access to the affected site, so lidocaine can be applied in clinical practice as an injection or local anti-cancer therapy.
"As a head and neck surgeon, we use lidocaine all the time," said co-corresponding author Ryan Carey. "We know lidocaine is safe, we feel comfortable using it, and it's readily available, which means it can be integrated fairly seamlessly into other aspects of head and neck cancer care."
The study also found that T2R14 is particularly high in HNSCC associated with human papillomavirus, which is currently the predominant form of HNSCC. We plan to conduct a clinical trial testing the effect of adding lidocaine to standard treatment of HPV-associated HNSCC.
"While we are not saying lidocaine can cure cancer, we are excited by its potential to gain advantages in the treatment of head and neck cancer and move forward in improving treatment options for patients with this challenging cancer," Carey said.
The research was published in the journal Cell Reports.