Potential targets for colorectal cancer prevention

Abstract

The step-wise development of colorectal neoplasia from adenoma to carcinoma suggests that specific interventions could delay or prevent the development of invasive cancer. Several key factors involved in colorectal cancer pathogenesis have already been identified including cyclooxygenase 2 (COX-2), nuclear factor kappa B (NF-κB), survivin and insulin-like growth factor-I (IGF-I). Clinical trials of COX-2 inhibitors have provided the "proof of principle" that inhibition of this enzyme can prevent the formation of colonic adenomas and potentially carcinomas, however concerns regarding the potential toxicity of these drugs have limited their use as a chemopreventative strategy. Curcumin, resveratrol and quercetin are chemopreventive agents that are able to suppress multiple signaling pathways involved in carcinogenesis and hence are attractive candidates for further research.

Figure 1

Mechanism of action of chemical compounds aspirin, metformin and NSAID (shown in green, dark blue and blue, respectively) and natural compounds curcumin, quercetin and resveratrol (shown in yellow, purple and red, respectively) in targeting pathways involved in colorectal carcinogenesis. COX-2: cyclooxygenase 2; AA: arachidonic acid; PGE₂: prostaglandin E₂; PGH₂: prostaglandin H₂; 15-PGDH: 15-prostaglandin dehydrogenase; P13K: phosphatidylinositol 3-kinase; TCF-4: T-cell factor 4; HIF-1: hypoxia inducible factor 1; MAPK: mitogen-activated protein kinase; BAX: Bcl-2 associated X protein; Bcl-2: B-cell lymphoma 2; TCF: T cell factor; Jak3: Janus kinase 3; stat3: signal transducer and activator of transcription 3; EGFR: epidermal growth factor receptor kinase; TNF-α: tissue necrosis factor α; ERK: extracellular signal-regulated protein kinase; IRS: insulin receptor substrate; Shc: Src-homology/collagen; TGF-β: transforming growth factor β; AMPK: adenosine monophosphate-activated protein kinase; mTOR: mammalian target of rapamycin; IL-1: interleukin 1; IKK: IKB kinase; IKB: inhibitor of NF-κB ; cytC: cytochrome C.