The novel capsazepine analog, CIDD‐99, significantly inhibits oral squamous cell carcinoma in vivo through a TRPV1‐independent induction of ER stress, mitochondrial dysfunction, and apoptosis

Background Oral squamous cell carcinoma (OSCC) is a deadly disease with a mere 40% five‐year survival rate for patients with advanced disease. Previously, we discovered that capsazepine (CPZ), a transient receptor potential channel, Vanilloid subtype 1 (TRPV1) antagonist, has significant anti‐tumor effects against OSCC via a unique mechanism‐of‐action that is independent of TRPV1. Thus, we developed novel CPZ analogs with more potent anti‐proliferative effects (CIDD‐24, CIDD‐99, and CIDD‐111). Methods Using OSCC xenograft models, we determined the efficacy of these analogs in vivo. TRPV1 interactions were evaluated using calcium imaging and a rat model of orofacial pain. Anti‐cancer mechanism(s)‐of‐action were assessed by cell cycle analysis and mitochondrial depolarization assays. Results CIDD‐99 was the most potent analog demonstrating significant anti‐tumor effects in vivo (P