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...

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Bibliographic Details
Published in:Journal of oral pathology & medicine 2019-05, Vol.48 (5), p.389-399
Main Authors: De La Chapa, Jorge J., Singha, Prajjal K., Self, Kristen K., Sallaway, McKay L., McHardy, Stanton F., Hart, Matthew J., McGuff, Howard Stan, Valdez, Matthew C., Ruiz, Francisco, Polusani, Srikanth R., Gonzales, Cara B.
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Calcium imaging
Capsaicin - analogs & derivatives
Capsaicin - pharmacology
Capsaicin receptors
Capsazepine
capsazepine analog
Carcinoma, Squamous Cell - drug therapy
Cell cycle
Cell Line, Tumor
Cell proliferation
Depolarization
Endoplasmic Reticulum Stress
Female
Humans
Isoquinolines - pharmacology
Male
Mice
Mice, Nude
Mitochondria
Mitochondria - drug effects
Mitochondria - pathology
Mouth Neoplasms - drug therapy
Oral cancer
Oral squamous cell carcinoma
Pain
Rats
Rats, Sprague-Dawley
Squamous cell carcinoma
Transient receptor potential proteins
TRPV Cation Channels - antagonists & inhibitors
Tumors
Xenograft Model Antitumor Assays
Xenografts
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Summary: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 
ISSN:0904-2512
1600-0714
DOI:10.1111/jop.12843