6-Gingerol delays tumorigenesis in benzo[a]pyrene and dextran sulphate sodium-induced colorectal cancer in mice
Introduction
Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer-related deaths worldwide (Bray et al., 2018). Several epidemiological studies have reported the role of pathological, environmental and dietary factors, such as ulcerative colitis, cigarette smoking, alcohol abuse, diets high in fat and low in fiber, a sedentary lifestyle and obesity as risk factors for the onset of CRC (Le Marchand et al., 1997; Harris et al., 2009; ). Benzo[a]pyrene (B[a]P, Fig. 1A) is a ubiquitous environmental pollutant that is associated with the development of CRC. Appreciable concentrations of B[a]P have been detected in cigarette smoke, charcoal-broiled meat, and industrial emissions (Lawal, 2017). Once inhaled or ingested via diet, B[a]P undergoes metabolic activation to reactive intermediates such as benzo[a]pyrene 7,8-oxide, benzo[a]pyrene-7,8-diol and benzo[a]pyrene diol epoxide that can form adducts with DNA (Ramesh et al., 2010; Moorthy et al., 2015). Several experimental investigations have reported that exposure to B[a]P alone or in combination with a colitogenic and tumor promoting agent, dextran sulphate sodium led to the induction of adenomas and adenocarcinomas in the colon of APCMin and CD2F1 mice (Banks et al., 2016; Diggs et al., 2013; Mantey et al., 2014). Consequently, investigating chemoprevention of B[a]P induced CRC is essential. In this regard, laboratory investigations have reported that natural compounds act as potential anti-carcinogenic agents by modulating certain biosignalling pathways that delay/block the occurrence and progression of CRC (Wu et al., 2018; Park and Pizzuto, 2002).
Ginger (Zingiber officinale Roscoe) belongs to the family Zingiberaceae. The rhizome of ginger has folkoric usage in traditional herbal medicine and the health-promoting effect of ginger is ascribed to the presence of various bioactive compounds such gingerols, shogaols, paradols, and zingerone (Mao et al., 2019). Ginger is generally regarded as safe by Food and Drug Administration (FDA) and it has been reported to be safe at doses of up to 4 g per day (Shukla and Singh, 2007; Ali et al., 2008). Several studies have reported the protective role of ginger and 6-G against inflammation and cancer. For instance, Ginger extract was shown to reduce LPS-induced inflammation through inhibition of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) activities as well as nuclear factor kappa B (NF-κB) activation (Manju and Nalini, 2005). In addition, treatment of the tumor cells with ginger resulted in decreases the expression of vascular endothelial growth factor (VEGF), activation of p53 and down regulation Bcl-2 expression (Liu et al., 2012).
6-Gingerol (6-G, Fig. 1B) is the most pharmacologically active agent in ginger. 6-gingerol has high bioavailability and it is metabolized to [6]-gingerol-4′-O-b-glucuronide following oral administration (Nakazawa and Ohsawa, 2002; Gundala et al., 2014). The LD50 of 6-G is 250 mg/kg (Suekawa et al., 1984). Furthermore, 6-G has been shown to induce apoptosis in gastric cancer cells by up regulating caspase-3 expression (Mansingh et al., 2018). Also, 6-G abridged the viability of gastric cancer cells through microtubules destruction (Ishiguro et al., 2007). In another study, 6-G suppressed proliferation of colon cancer (HCT116) cells through inhibition of leukotriene A4 hydrolase activity (Jeong et al., 2009). Additional mechanistic pathways such as downregulation of cyclin D1, NAG-1, PKC and GSK-3β pathways were also described for 6-G induced apoptosis in human colorectal cancer cell lines (Lee et al., 2008). Moreover, 6-G inhibited cell proliferation and induced apoptosis through activation of caspases 3 and G1/S cell cycle arrest with subsequent down regulation of the cyclin D1 in HCT116 cells (Lee et al., 2008). Furthermore, 6-G suppressed COX-2 expression by blocking p38 MAPK–NF–kB signaling (Kim et al., 2004).
Recently in our laboratory, we demonstrated the beneficial effects of 6-G in mice model of acute and chronic ulcerative colitis, (UC), an inflammatory disease of the colon that predisposes to CRC (Ajayi et al., 2015). We reported that 6-G elicited its modulatory effect on UC via reduction of oxidative stress indices and systemic concentration of tumor necrosis factor alpha, interleukin-1β, NF-κB (P65), p38 and COX-2 (Ajayi et al., 2018). More recently, we showed that 6-G abated B[a]P-induced colonic injury via suppression of oxido-inflammatory stress responses and facilitated B[a]P epoxide detoxification in mice (Ajayi et al., 2019). The present study therefore investigated the effect of 6-G on B[a]P and DSS-induced CRC in mice.
Section snippets
Materials
Dextran Sulphate Sodium (DSS) (molecular weight 37–40 kD) was procured from TdB Consultancy, (Uppsala, Sweden), benzo[a]pyrene was purchased from Sigma Aldrich co UK, anti-RANTES, anti-MCP-1, anti-tumor necrosis factor alpha (TNF-α), anti-cyclooxygenase-2 (COX-2), anti-nuclear factor kappa B, P65 (NF-κB (P65), anti-inducible nitric oxide synthase (iNOS), anti-p38 (mitogen-activated protein kinase, MAPK), anti-interleukin-1β (IL-1β), anti-β-catenin and anti-adenomatous polyposis coli (APC) mouse
6-Gingerol suppresses tumor growth and tumor incidence in Benzo[a]pyrene/dextran sulphate sodium-induced colorectal cancer
Fig. 1D depicts the gross macroscopic appearance high incidence of colon tumour numbers in B[a]P + DSS-treated mice. There were marked decrease in tumor numbers following exposure to 6-G when compared with the B[a]P + DSS-treated mice. Histological examination of B[a]P + DSS-treated mice colon revealed a typical gland Adenocarcinoma with bizzare cells, cells with pleiomorphism, prominent nucleoli and vascular nuclei and severe disseminated inflammation affecting the mucosa, submucosa,
Discussion
Several studies have linked the development of CRC to dietary consumption of B[a]P (Harris et al., 2016). In addition, we have previous demonstrated the activation of early events associated with CRC development following oral exposure of B[a]P to BALB/c mice. We showed that B[a]P induces oxidative stress, pro-inflammatory cytokines, expression of nuclear factor-kappa B and deregulation of Wnt/β-catenin signaling in colons of exposed mice (Ajayi et al., 2016). Suppression of inflammation and
CRediT authorship contribution statement
Ebenezer O. Farombi: Writing - review & editing, Conceptualization, Funding acquisition, Supervision. Babajide O. Ajayi: Data curation, Formal analysis, Visualization, Writing - original draft. Isaac A. Adedara: Formal analysis, Validation.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgement
This work was supported by the TETFUND (Nigeria) Institutional Based Research (IBR) grant awarded to Professor E.O. Farombi.
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