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

Jorge J. De La Chapa, Prajjal K. Singha, Kristen K. Self, McKay L. Sallaway, Stanton F. McHardy, Matthew J. Hart, Howard S Mcguff, Matthew C. Valdez, Francisco Ruiz, Srikanth R. Polusani, Cara B. Gonzales

Producción científica: Articlerevisión exhaustiva

9 Citas (Scopus)

Resumen

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.

Idioma originalEnglish (US)
Páginas (desde-hasta)389-399
Número de páginas11
PublicaciónJournal of Oral Pathology and Medicine
Volumen48
N.º5
DOI
EstadoPublished - may 2019

ASJC Scopus subject areas

  • Oral Surgery
  • Periodontics
  • Cancer Research
  • Pathology and Forensic Medicine
  • Otorhinolaryngology

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