Abstract A39: 6-Gingerol, a chemopreventive phytochemical as speed breaker in inflammatory and stress signaling cascade triggered by benzo(a)pyrene and dextran sulphate sodium-mediated colorectal cancer in mice

Abstract

Abstract Preclinical and clinical investigations have identified unresolved inflammation and oxidative/nitrosative stress as two coconspirators, which play a multifaceted role and serve as driving force in the journey to cancer development. Ulcerative colitis is an inflammatory disease of the colon that predisposes to colorectal cancer, the fourth leading cause of cancer worldwide. Overexpression of proinflammatory mediators, a distinct network of intracellular signaling molecules including upstream kinases and transcription factors, facilitates tumor promotion and CRC progression. Current therapeutic drugs for CRC have severe adverse effects. Several investigations indicate that a plant-based diet rich in a wide variety of fruits and vegetables is effective in preventing or reversing premalignant lesions. Thus, the search for novel chemopreventive agents of physiologic relevance acting on specific and/or multiple molecular and cellular targets holds promise as a rational strategy for the control of health-threatening diseases such as ulcerative colitis and CRC. A bioactive component, 6-gingerol from ginger (Zingiber officinale) has been reported to possess antioxidant and anti-inflammatory activities. Our study demonstrates that 6-gingerol protects against dextran sulfate sodium (DSS)-induced ulcerative colitis in BalBc mice. 6-Gingerol attenuated DSS-mediated increase in immunoexpression of nuclear factor kappa B (NF-κB [p65]), tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1 β), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), mitogen-activated kinase (P 38), RANTES, Bcl2, monocyte chemoattractant protein (MCP-1), and β-catenin expression. Similarly, 6-gingerol modulated DSS decrease in adenomatous polyposis coli (APC), DESMIN, Interleukin 10, and levels of antioxidant enzymes. In the two-stage (DMBA initiation and TPA promotion) mouse skin carcinogenesis model, 6-gingerol downregulated the expression of COX-2 and NF-κB. Also, in the benzo(a)pyrene and DSS (BDS) model of colorectal cancer, BDS induced adenocarcinoma and decreased APC, p53 expression, and number of apoptotic cells. In addition, tumor incidence, β-catenin, and cyclin D1 expressions were increased. Treatment with 6-gingerol decreased adenocarcinoma significantly and modulated the expression of these proteins and transcription factors. This anti-inflammatory phytochemical exerted chemopreventive effects by modulating intracellular signaling cascades and proinflammatory mediators and therefore qualifies as therapeutic signature for chemoprevention of inflammation-associated CRC. Citation Format: Ebenezer O. Farombi, Babajide O. Ajayi, Isaac A. Adedara, Solomon E. Owumi. 6-Gingerol, a chemopreventive phytochemical as speed breaker in inflammatory and stress signaling cascade triggered by benzo(a)pyrene and dextran sulphate sodium-mediated colorectal cancer in mice [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A39.