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.

Autor: De La Chapa JJ; Department of Comprehensive Dentistry, School of Dentistry, UT Health San Antonio, San Antonio, Texas., Singha PK; Department of Pathology, School of Medicine, UT Health San Antonio, San Antonio, Texas., Self KK; Department of Comprehensive Dentistry, School of Dentistry, UT Health San Antonio, San Antonio, Texas., Sallaway ML; Department of Comprehensive Dentistry, School of Dentistry, UT Health San Antonio, San Antonio, Texas., McHardy SF; Center for Innovative Drug Discovery, Department of Chemistry, University of Texas at San Antonio, San Antonio, Texas.; Mays Cancer Center, UT Health San Antonio, San Antonio, Texas., Hart MJ; Mays Cancer Center, UT Health San Antonio, San Antonio, Texas.; Center for Innovative Drug Discovery, HTS Facility, Department of Biochemistry and Structural Biology, UT Health San Antonio, San Antonio, Texas., McGuff HS; Department of Pathology, School of Medicine, UT Health San Antonio, San Antonio, Texas., Valdez MC; Center for Innovative Drug Discovery, Department of Chemistry, University of Texas at San Antonio, San Antonio, Texas., Ruiz F 2nd; Center for Innovative Drug Discovery, Department of Chemistry, University of Texas at San Antonio, San Antonio, Texas., Polusani SR; Center for Innovative Drug Discovery, HTS Facility, Department of Biochemistry and Structural Biology, UT Health San Antonio, San Antonio, Texas., Gonzales CB; Department of Comprehensive Dentistry, School of Dentistry, UT Health San Antonio, San Antonio, Texas.; Mays Cancer Center, UT Health San Antonio, San Antonio, Texas.
Jazyk: angličtina
Zdroj: Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology [J Oral Pathol Med] 2019 May; Vol. 48 (5), pp. 389-399. Date of Electronic Publication: 2019 Apr 04.
DOI: 10.1111/jop.12843
Abstrakt: 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.
(© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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