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Novel polygodial analogs P3 and P27: Efficacious therapeutic agents disrupting mitochondrial function in oral squamous cell carcinoma

Citation

De La Chapa, J and Singha, PK and Sallaway, M and Self, K and Nasreldin, R and Dasari, R and Hart, M and Kornienko, A and Just, J and Smith, JA and Bissember, AC and Gonzales, CB, Novel polygodial analogs P3 and P27: Efficacious therapeutic agents disrupting mitochondrial function in oral squamous cell carcinoma, International Journal of Oncology, 53, (6) pp. 2627-2636. ISSN 1019-6439 (2018) [Refereed Article]

Copyright Statement

Copyright 2018 International Journal of Oncology

DOI: doi:10.3892/ijo.2018.4585

Abstract

Polygodial, a drimane sesquiterpenoid dialdehyde isolated as a pungent component of the water pepper Persicaria hydropiper, exhibits antifeedant, antimicrobial, anti-inflammatory and anticancer effects. Polygodial also activates transient receptor potential vanilloid subtype 1 (TRPV1) channels. Previously, we described the synthesis of a C12-Wittig derivative of polygodial, termed P3, with significant antiproliferative effects against multiple cancer types including oral squamous cell carcinoma (OSCC). In the present study, a more potent derivative, P27, with superior anti-proliferative effects in vitro and antitumor effects in Cal-27 derived xenografts is described. Polygodial, P3, and P27 all significantly decreased OSCC tumor growth, with P27 being equipotent with polygodial and P3 being the least efficacious. However, neither analog elicited the adverse effect observed with polygodial: Profound transient inflammation. Although P3 and P27 pharmacophores are based on polygodial, novel effects on OSCC cell cycle distribution were identified and shared anticancer effects that are independent of TRPV1 activity were observed. Polygodial elicits an S-phase block, whereas P3 and P27 lead to G2/M phase arrest. Pretreatment of OSCC cells with the TRPV1 antagonist capsazepine does not affect the antiproliferative activity of P3 or P27, indicating that TRPV1 interactions do not regulate OSCC cell proliferation. Indeed, calcium imaging studies identified that the analogs neither activate nor antagonize TRPV1. Behavioral studies using a rat model for orofacial pain confirmed that these analogs fail to induce nocifensive responses, indicating that they are non-noxious in vivo. All compounds induced a significant concentration-dependent decrease in the mitochondrial transmembrane potential and corresponding apoptosis. Considering that P27 is equipotent to polygodial with no TRPV1-associated adverse effects, P27 may serve as an efficacious novel therapy for OSCC.

Item Details

Item Type:Refereed Article
Keywords:polygodial, oral squamous cell carcinoma, mitochondrial dysfunction, apoptosis anti-inflammatory, anticancer
Research Division:Chemical Sciences
Research Group:Organic Chemistry
Research Field:Organic Chemical Synthesis
Objective Division:Expanding Knowledge
Objective Group:Expanding Knowledge
Objective Field:Expanding Knowledge in the Chemical Sciences
UTAS Author:Just, J (Mr Jeremy Just)
UTAS Author:Smith, JA (Associate Professor Jason Smith)
UTAS Author:Bissember, AC (Dr Alex Bissember)
ID Code:128880
Year Published:2018
Deposited By:Chemistry
Deposited On:2018-10-20
Last Modified:2019-03-07
Downloads:0

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