Journal
MOLECULAR CARCINOGENESIS
Volume 52, Issue 3, Pages 195-206Publisher
WILEY
DOI: 10.1002/mc.21843
Keywords
NF-B signaling; colorectal cancer; chemoprevention; silibinin
Categories
Funding
- NCI [CA112304]
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Chronic inflammation is one of the primary causes of colorectal cancer (CRC), and major inflammatory pathways implicated in CRC are cyclooxygenase-2 (COX-2) and iNOS; both regulated by nuclear factor-kappa B (NF-B) suggesting that inhibitors of these pathways could be ideal against CRC. Silibinin has shown promising efficacy against various malignancies including CRC, and therefore here we assessed whether silibinin targets NF-B activation and associated signaling as a mechanism of its anti-inflammatory and anti-cancer effects in CRC. Our results indicated that silibinin treatment (50200 mu M) of human CRC SW480, LoVo, and HT29 cells strongly inhibits tumor necrosis factor -induced NF-B activation together with decreased nuclear levels of both p65 and p50 sub-units. Silibinin also significantly increased IB level with a concomitant decrease in phospho-IB, without any effect on TNFR1, TRADD, and RIP2, indicating its inhibitory effect on IB kinase activity. Next we assessed the effect of oral silibinin feeding on NF-B pathway in SW480 (COX-2 negative) and LoVo (COX-2 positive) tumor xenografts in nude mice. Together with its inhibitory efficacy on tumor growth and progression, silibinin inhibited NF-B activation in both xenografts. The protein levels of various NF-B-regulated molecules such as Bcl-2, COX-2, iNOS, VEGF, and MMPs were also decreased by silibinin in both cell culture studies and xenograft analyses, suggesting its potential to alter NF-B transcriptional activity. Together, these findings are highly significant in establishing for the first time that silibinin suppresses CRC growth and progression possibly through its anti-inflammatory activity by interfering with NF-B activation and thus has potential against human CRC. (c) 2011 Wiley Periodicals, Inc.
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