Inflammatory bowel disease (IBD) is comprised of ulcerative colitis (UC) and Crohn's disease (CD) that was recognized by the inflammation in the colon. There are no proper medications are available to control the IBD in patients. NASIDs such as Aspirin, diclofenac, and ibuprofen are widely used to control the inflammation. On the other hand, the untreated prolonged inflammation leads to the development of cancer in the colon termed as colitis-associated cancer or inflammation-driven colon cancer. Oxidative stress and inflammation play key roles in the pathogenesis of colitis-associated cancer. Single dose of azozymethane (AOM) and three cycles of 2% dextran sodium sulfate (DSS) induces colitis-associated cancer (CAC) in mouse. Hence, many natural products were tested in the preclinical model of colitis-associated cancer. Each of these natural agents modulate important signaling pathway to control the colitis-associated cancer (CAC). In this review, the authors tabulated all the natural agents that culminate the colitis-associated cancer in the preclinical models.
TopIntroduction
Inflammatory bowel disease (IBD) is sub categorized into two major diseases namely ulcerative colitis (UC) and Crohn’s disease (CD). The incidence of UC worldwide is in a steady rise due to the intake of unbalanced diet. It has been reported that UC is associated with an increased levels of various inflammatory markers such as myeloperoxidase (MPO), interleukin (IL)-1β, IL-6, IL-17, IL-21, tumor necrosis factor-alpha (TNF-α), nuclear factor-kappa B (NF-κB), Inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). It was also known that untreated chronic inflammation in the colon leads the development of colitis associated cancer (CAC) (Pandurangan and Esa, 2014). There several signalling pathways were identified in the transformation of UC to colitis associated cancer. Oxidative stress plays a vital role in the pathogenesis of UC. Hence, many natural products that possess antioxidant ability were used for the treatment of UC in the preclinical level (Pandurangan et al., 2015; Pandurangan et al., 2015a; Pandurangan et al., 2016). So far, Non-steroidal anti-inflammatory drugs such as 5-aminosalicylic acid (5-ASA), Balsalazide, mesalamine, olsalazine, and sulfasalazine were used in the treatment of UC. Still, the research is underway to find suitable drug to treat UC without any side effects.
The pathogenesis of CAC was explained in derail in many published reports (Figure 1). When a normal epithelium undergo injury by the production of reactive oxygen species by various environmental mutagens. This injury leads to the formation of aberrant crypt foci (ACF) which is considered as a pre-neoplastic lesion of Colorectal cancer. Several pro-inflammatory cytokines
NF-κB Pathway and Colitis Associated Cancer
The development of inflammation-related cancer is a long period of tumor promotion, and persistent inflammation facilitates tumor formation by activating the proliferation and antiapoptotic properties of premalignant cells. Moreover, the localized inflammatory microenvironment can promote accumulation mutations and genetic changes after tumor formation. Many reports have documented the critical link between inflammation and the development of CRC. Among the many signaling pathways that are involved in colonic inflammation, the NF-κB pathway is central. NF-κB proteins are involved in the control of many normal cellular and physiological processes, including immune and inflammatory responses, developmental processes, cellular growth and apoptosis.
STAT3 Signaling and Colitis Associated Cancer
Signal transducer and activator of transcription (STAT) 3 protein is a member of the STAT family of transcription factors, which are initially located in the cytoplasm in their inactive form. After stimulation by extracellular signals, such as cytokines, growth factors and hormones, Janus kinases (AKs) are activated and then induce the phosphorylation of STAT3 at tyrosine residue 705 (Y705) . Phosphorylated STAT3 proteins dimerize via their Src-homology 2 (SH2) domains and translocate to the nucleus, where they regulate the expression of numerous critical genes involved in cell-cycle progression, proliferation, migration, invasion and survival. However, the constitutive activation of STAT3 is frequently detected in clinical samples from a wide range of human carcinoma, particularly CRC. Hence, STAT3 is considered the most important target of chemoprevention and therapy in CAC.