@article{56706b9c1daf44b6bbabe333b158b06e,
title = "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",
abstract = "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 < 0.001). CIDD-24 was equipotent to the parent compound CPZ, but less potent than CIDD-99. CIDD-111 was the least efficacious analog. Calcium imaging studies confirmed that CIDD-99 neither activates nor inhibits TRPV1 confirming that TRPV1 activity is not involved in its anti-cancer effects. All analogs induced an S-phase block, dose-dependent mitochondrial depolarization, and apoptosis. Histological analyses revealed increased apoptosis and reduced cell proliferation in tumors treated with these analogs. Importantly, CIDD-99 had the most dramatic anti-tumor effects with 85% of tumors resolving leaving only minute traces of viable tissue. Additionally, CIDD-99 was non-noxious and demonstrated no observable adverse reactions. Conclusion: This study describes a novel, highly efficacious, CPZ analog, CIDD-99, with dramatic anti-tumor effects against OSCC that may be efficacious as a lone therapy or in combination with standard therapies.",
keywords = "capsazepine analog, mitochondria, oral cancer",
author = "{De La Chapa}, {Jorge J.} and Singha, {Prajjal K.} and Self, {Kristen K.} and Sallaway, {McKay L.} and McHardy, {Stanton F.} and Hart, {Matthew J.} and McGuff, {Howard Stan} and Valdez, {Matthew C.} and Francisco Ruiz and Polusani, {Srikanth R.} and Gonzales, {Cara B.}",
note = "Funding Information: This work was supported by the National Center for Advancing Translational Sciences, National Institutes of Health (NIH), through Grant UL1 TR002645. This work was also supported by the UT Health San Antonio Mays Cancer Center. FACs analysis was performed at the Mays Cancer Center Flow Cytometry Core Facility supported by a National Cancer Institute (NCI) Cancer Center Support Grant P30 CA054174. Work performed in the Center for Innovative Drug Discovery High Throughput?Screening Facility was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant?UL1 TR001120. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Funding Information: National Center for Advancing Translational Sciences; National Institutes of Health NIH, Grant/Award Number: UL1 TR002645 and UL1 TR001120; UT Health San Antonio Mays Cancer Center; National Cancer Institute NCI Cancer Center, Grant/Award Number: P30 CA054174 Funding Information: This work was supported by the National Center for Advancing Translational Sciences, National Institutes of Health (NIH), through GrantUL1TR002645.ThisworkwasalsosupportedbytheUTHealth San Antonio Mays Cancer Center. FACs analysis was performed at the Mays Cancer Center Flow Cytometry Core Facility supported by a National Cancer Institute (NCI) Cancer Center Support Grant P30 CA054174. Work performed in the Center for Innovative Drug Discovery High Throughput Screening Facility was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1 TR001120. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.",
year = "2019",
month = may,
doi = "10.1111/jop.12843",
language = "English (US)",
volume = "48",
pages = "389--399",
journal = "Journal of Oral Pathology and Medicine",
issn = "0904-2512",
publisher = "Wiley-Blackwell",
number = "5",
}