Unlocking the Potential of CIDD-99: A Novel TRPV1-Independent Approach to Combat Oral Squamous Cell Carcinoma

The study focuses on oral squamous cell carcinoma (OSCC), a severe condition with a low survival rate. Researchers have found that capsazepine (CPZ), a TRPV1 antagonist, has anti-tumor effects on OSCC that are not dependent on TRPV1. To enhance this effect, new CPZ analogs with stronger anti-proliferative properties were developed, namely CIDD-24, CIDD-99, and CIDD-111.

Experiments using OSCC xenograft models were conducted to evaluate the in vivo effectiveness of these analogs. The role of TRPV1 was examined through calcium imaging and a rat pain model. The anti-cancer mechanisms were studied using cell cycle analysis and mitochondrial depolarization tests.

The results showed that CIDD-99 was the most effective analog with significant in vivo anti-tumor effects (P < 0.001). CIDD-24 had similar potency to CPZ but was less potent than CIDD-99. CIDD-111 was the least effective. Calcium imaging confirmed that CIDD-99 does not interact with TRPV1, indicating that its anti-cancer effect is independent of TRPV1 activity. All analogs caused an S-phase block, dose-dependent mitochondrial depolarization, and apoptosis. Histological analysis showed increased apoptosis and reduced cell proliferation in treated tumors. Notably, CIDD-99 had the most striking anti-tumor impact, with 85% of tumors resolving and only minimal viable tissue remaining. Moreover, CIDD-99 was found to be non-irritating and without any observable adverse effects.

The research concludes with the identification of a new, highly effective CPZ analog, CIDD-99, which has remarkable anti-tumor effects against OSCC. It suggests that CIDD-99 could be a potential standalone therapy or used in conjunction with standard treatments.