title: Effect of silibinin in human colorectal cancer cells: targeting the activation of NF-κB signaling.
abstract: 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-κB) 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-κB activation and associated signaling as a mechanism of its anti-inflammatory and anti-cancer effects in CRC. Our results indicated that silibinin treatment (50-200 µM) of human CRC SW480, LoVo, and HT29 cells strongly inhibits tumor necrosis factor α-induced NF-κB activation together with decreased nuclear levels of both p65 and p50 sub-units. Silibinin also significantly increased IκBα level with a concomitant decrease in phospho-IκBα, without any effect on TNFR1, TRADD, and RIP2, indicating its inhibitory effect on IκB kinase α activity. Next we assessed the effect of oral silibinin feeding on NF-κB 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-κB activation in both xenografts. The protein levels of various NF-κB-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-κB 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-κB activation and thus has potential against human CRC.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, Aurora, Colorado 80045, USA.
authors.forename: Komal
authors.initials: K
authors.lastname: Raina
authors.forename: Chapla
authors.initials: C
authors.lastname: Agarwal
authors.forename: Rajesh
authors.initials: R
authors.lastname: Agarwal
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D004354:Drug Screening Assays, Antitumor; D019073:HT29 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016328:NF-kappa B; D012838:Silymarin; D014409:Tumor Necrosis Factor-alpha; D000077385:Silybin
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