Synergistic growth inhibition of mouse skin tumors by pomegranate fruit extract and diallyl sulfide: Evidence for inhibition of activated MAPKs/NF-κB and reduced cell proliferation

Limited outcomes from earlier chemopreventive studies have necessitated that some modifications be made to get better efficacy. It is proposed that cancer prevention is more feasible than treatment, and this could be achieved effortlessly with use of multiple agents competent of targeting multiple targets. This study was initiated to examine the chemopreventive efficacy of pomegranate fruit extract (PFE) and diallyl sulfide (DAS), alone and in combination, using 2-stage mouse skin tumorigenesis model. PFE and DAS alone delayed onset and tumor incidence by ∼55% and ∼45%, respectively, while their combination at low doses synergistically decreased tumor incidence more potentially (∼84%, p < 0.01). In addition, regression in tumor volume was seen with continuous combinatorial treatment (p < 0.01). Mechanistic studies revealed that this inhibition was associated with decreased expression of phosphorylated ERK1/2, JNK1 and activated NF-κB/p65, IKKα, IκBα phosphorylation and degradation in skin tissue/tumor. Histological and cell death analysis also confirmed that combined PFE and DAS inhibit cellular proliferation and markedly induce apoptosis than the single agents. Altogether, our results suggest that PFE and DAS in combination impart better suppressive activity than either of these agents alone and provide support that development of novel combination therapies/chemoprevention using dietary agents will be more beneficial against cancer.