Lidocaine Unleashes Cancer-Combatting Apoptosis in HNSCCs Through T2R14 Activation

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Head and neck squamous cell carcinomas (HNSCCs) represent a significant global health burden, originating in the mucosa of oral and nasal cavities, larynx, and pharynx. The annual incidence of HNSCCs is approximately 900,000, with a staggering 5-year mortality rate of around 50%.

Late-stage diagnosis, lack of preventive screening, and high metastatic rates contribute to this alarming mortality rate. Current treatment modalities, including surgery, radiation, chemotherapy, and immunotherapy, often result in severe side effects, impacting patients’ quality of life (QoL). This underscores the urgent need for innovative, targeted therapies that not only effectively treat HNSCC but also preserve patients’ QoL.

Localization of HNSCCs and Taste Perception:

The majority of HNSCCs are localized to the oral cavity and oropharynx, regions crucial for taste perception. Humans can perceive five tastes: sour, salty, sweet, umami, and bitter. Sweet, umami, and bitter tastes are mediated by specialized G-protein-coupled receptors (GPCRs), specifically taste family 1 (T1Rs) for sweet and umami, and taste family 2 (T2Rs) for bitter. Of the 25 T2R isoforms in humans, T2R14 has been extensively studied.

T2Rs Beyond Taste Perception:

While T2Rs play a role in bitter taste perception, they are also involved in innate immunity, thyroid function, cardiac physiology, and various biological processes. Previous studies have linked T2Rs to cancers, including ovarian, breast, and HNSCC. T2R14, in particular, has been a focus of research due to its involvement in bitter taste perception and other biological functions.

Lidocaine and T2R14 Activation:

Lidocaine, a commonly used local anesthetic, has been explored for its potential anticancer effects, with some studies suggesting a decrease in metastasis rates in certain malignancies. Intriguingly, lidocaine is bitter and activates T2R14. This led to the hypothesis that lidocaine may induce pro-apoptotic effects in HNSCCs through T2R14.

Experimental Findings:

Research findings reveal that lidocaine indeed induces Ca2+ responses in HNSCC cells through T2R14 activation. Furthermore, lidocaine decreases cell viability, depolarizes mitochondrial membrane potential (MMP), elevates mitochondrial reactive oxygen species (ROS), and induces apoptosis. Importantly, specific T2R14 antagonists block lidocaine-induced apoptosis. The study also uncovers that lidocaine inhibits the proteasome in a T2R14-dependent manner, suggesting a novel link between GPCR signaling and proteasome inhibition.

Therapeutic Implications:

These findings propose lidocaine as a potential therapeutic for HNSCCs, either through topical gel application or intratumor injection. The study suggests that HPV-associated (HPV+) HNSCCs, which exhibit increased expression of TAS2R14 (the gene encoding T2R14), may particularly benefit from T2R14 activation.

Discussion

Head and neck squamous cell carcinomas (HNSCCs) present a formidable challenge in terms of prognosis, with roughly half of patients surviving past 5 years even with available treatments. Standard therapeutic options, including surgery, radiotherapy, and chemotherapy, often result in lasting effects, emphasizing the need for innovative and targeted therapies. The limitations of current targeted therapies, such as immune checkpoint inhibitors and EGFR inhibitors, underscore the necessity to discover novel treatments with favorable side effect profiles for HNSCC.

The data presented in this study propose a promising avenue for addressing this urgent need. Targeting bitter taste receptors (T2Rs), specifically leveraging existing clinical compounds like the local anesthetic lidocaine, demonstrates potential as a therapeutic strategy against HNSCCs. T2R agonists, including lidocaine, exhibit detrimental effects on HNSCC cellular function, mitochondrial membrane potential (MMP), and cell survival. The upregulation of TAS2R14 expression in some HNSCC cases suggests the possibility of a personalized treatment approach based on receptor expression.

An intriguing aspect of the study is the revelation of the mechanism underlying lidocaine-induced apoptosis in HNSCC cells. Unlike other anesthetics with similar sodium channel-blocking abilities, lidocaine activates apoptosis specifically in some cancer cells. The study establishes a connection between lidocaine and endogenous T2R14 in HNSCC cells, with lidocaine-induced Ca2+ responses surpassing those of other T2R agonists. The downstream signaling pathways involved in lidocaine-induced apoptosis, including the decrease in cAMP, GPCR activation, and proteasome inhibition, provide valuable insights into the molecular mechanisms at play.

Furthermore, the study explores the potential of lidocaine as an easily translatable compound for clinical use. With its high solubility, documented safety data, and known beneficial palliative effects, lidocaine emerges as a promising candidate for repurposing as an anticancer therapy. The accessibility of mucosal sites affected by HNSCCs, where bitter agonists like lidocaine can be easily implemented, adds to the attractiveness of this therapeutic approach.

The discussion also delves into the specifics of T2R14 activation by lidocaine, presenting evidence of GPCR activation, secondary messenger involvement, and distinct signaling pathways compared to other T2R agonists. The study emphasizes the importance of T2R14 activation in lidocaine-induced apoptosis, supported by the dampening of responses with T2R14 antagonists and CRISPR targeting.

The link between GPCR activation and proteasome inhibition uncovered in this study is a notable contribution to the understanding of the molecular events leading to apoptosis. The potential pro-apoptotic mechanisms beyond proteasome inhibition suggest a multifaceted impact of T2R14 activation on HNSCC cells. The study also highlights the uniqueness of lidocaine-induced proteasome inhibition, dependent on T2R14 signaling rather than direct proteasome binding.

As the discussion concludes, the study calls for further in vivo and clinical investigations to validate the potential therapeutic use of lidocaine in treating HNSCCs. The broad applicability of lidocaine, evident in its effectiveness against both HPV+ and HPV- HNSCC cells, underscores its potential as a versatile treatment option. The proposed delivery methods, including topical gel or local injection during surgical resection, align with recent successful strategies in other cancer types.

The study’s insights into T2R14 therapies, potential synergies with existing treatments, and the importance of personalized medicine based on tumor expression profiling contribute significantly to the ongoing efforts to improve outcomes for HNSCC patients. The detailed exploration of lidocaine as a repurposable compound and the identification of T2R14 as a potential therapeutic target provide a solid foundation for future research and clinical applications.


reference link : https://www.cell.com/cell-reports/fulltext/S2211-1247(23)01449-3#secsectitle0075

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