Abstract
Chemoprevention is cost-effective for colorectal cancer when targeted at intermediate- or high-risk populations. Bufalin is a cardiac glycoside extracted from the traditional Chinese medicine (TCM) "Chan Su," which has been used as an anticancer agent. On the basis of the relative safety of bufalin, we investigated whether bufalin could act as a chemoprophylactic agent to prevent colon tumorigenesis in two murine models, namely colitis-associated colorectal cancer and Apc germline mutation-developed colorectal cancer. Our results revealed that long-term (12-16 weeks) administration of low-dose bufalin (0.5 mg/kg) effectively suppressed tumorigenesis in both colorectal cancer models, accompanied by attenuated epithelial cell proliferation (reduced bromodeoxyuridine incorporation, lower levels of cyclin A, cyclin D1, cyclin E, and cyclin-dependent kinases-2/4, and higher levels of p21 and p27) and promoted apoptosis (increased TUNEL positivity and caspase-3/9 cleavages, reduced levels of Bcl-2, Bcl-xL and survivin, and increased levels of Bax and Bak). Bufalin also suppressed the expression of proinflammatory mediators [reduced levels of cyclooxygenase-2, tumor TNFα, IL1β, IL6, C-X-C motif chemokine ligand (CXCL)-1, CXCL-2, and CXCL-5] in the colitis-associated colorectal cancer model. These effects were associated with the inhibition of oncogenic NF-κB and PI3K/Akt pathways. Our findings unveil a novel chemoprophylactic action of bufalin in colorectal cancer in vivo and provided efficacy data and mechanistic evidence for further clinical evaluation of this TCM compound for colorectal cancer chemoprevention in individuals at risk of colorectal cancer.
Highlights
Colorectal cancer has become the third leading cause of cancer-related death among all fatal cancer types worldwide [1]
To investigate the role of bufalin in colorectal cancer, two murine models of colon tumorigenesis had been adopted, viz colitis-associated colorectal cancer and colonic tumors induced by adenomatous polyposis coli (Apc) germline mutation, which resemble inflammatory and genetically predisposed pathways of colorectal cancer in humans, respectively
Did not show extensive alterations in body weight loss compared to the dextran sulphate sodium (DSS)-vehicle group (Supplementary Fig. S1A)
Summary
Colorectal cancer has become the third leading cause of cancer-related death among all fatal cancer types worldwide [1]. Colonic tumorigenesis is driven by chronic inflammation which is another key promoter of colorectal cancer This prolonged low-grade inflammatory response involves a progressive change in the type of cells present at the site of inflammation and continuous production of DNA-damaging oxygen radical species, extracellular matrix-modifying enzymes and growth factors which can infiltrate into the local mucosal tissue in the colon, leading to a microenvironment conducive to tumorigenesis [5]. Given the fact that it takes years to decades for normal mucosa developing into carcinoma, a window of opportunity, is offered to prevent the incipient morbidity of colorectal cancer by employing proper interventions [6]. At this point, the concept of chemoprevention is highlighted once again in recent decades. Chemopreventive agents are many and can be classified into various modalities, including non-toxic www.aacrjournals.org naturally occurring compounds, dietary extracts and synthetic pharmacotherapeutic compounds
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