To study the chemopreventive potential of piperlongumine and role of NF KB and its target genes in experimental colon cancer

Abstract

Chronic inflammation is now an established enabling hallmark of cancer. Amongst the various signaling pathways involved in colonic chronic inflammation, nuclear factor-and#954;B (NF-and#954;B) signaling pathway plays the central role by upregulating expression of cytokines and growth factors released during chronic inflammation. Piperlongumine (PL, piplartine), a piper alkaloid found in the fruit of the long pepper (Piper longum Linn.) has gained worldwide attention for its anticancer properties, however, its mechanism of action has not been fully elucidated in colon cancer. In the current study, chemopreventive potential of PL has been explored using DMH/DSS induced murine model of colon carcinogenesis. Analysis of early tumor biomarkers such as alteration in colon histology, mucin content, TSA, LASA, LDH levels and oxidative stress parameters suggested the antineoplastic activity of PL. Next, results of cell death and cell proliferation assays further potentiated the chemopreventive properties of PL. On mechanistic part, PL was found to inhibit NF-and#954;B activation as well as its nuclear translocation. Further investigation revealed that PL also diminished the phosphorylation of its inhibitory subunit i.e. Iand#954;B. We also observed inhibition of COX-2 and its downstream pro- inflammatory products including PGD2S and PGES2 on PL treatment. The results of CAM assay, VEGF and MMP-9 levels suggested that PL potently inhibited vasculogenesis/angiogenesis and tumor invasion. There was also a diminution in metastatic potential as a significant increase in E-cadherin levels and reduction in levels of snail, TCF/Zeb, vimentin and N-cadherin were observed with the treatment regimen. Biochemical and histological studies related to liver and kidney suggested that daily administration of PL was nontoxic to animals at a dose of 3.6 mg/kg body weight. Collectively, PL seems to be an attractive bioactive phytochemical with pleiotropic action for prevention of colon cancer.