title: Restoration of the anti-proliferative and anti-migratory effects of 1,25-dihydroxyvitamin D by silibinin in vitamin D-resistant colon cancer cells.
abstract: Colorectal carcinoma (CRC) is the third most common cancer in developed countries. A large fraction of cases are linked to chronic intestinal inflammation, with concomitant increased TNF-α release and elevated Snail1/Snail2 levels. These transcription factors in turn suppress vitamin D receptor (VDR) expression, resulting in loss of responsiveness to the protective anti-proliferative and anti-migratory effects of 1,25-dihydroxyvitamin D (1,25D). Experimental and epidemiologic evidence support the use of natural products to target CRC. Here we show that the flavonolignan silibinin reverses the TNF-α-induced upregulation of Snail1 and Snail2 in the 1,25D-resistant human colon carcinoma cells HT-29. These silibinin effects are accompanied by an increase in VDR levels; Snail1 overexpression reverses these silibinin effects. Silibinin also restores promoter activity from a vitamin D-response element (VDRE) reporter construct. While 1,25D had no significant effect on HT-29 and SW480-R cell proliferation and migration, co-treatment with silibinin restored 1,25D responsiveness. In addition, co-treatment with silibinin plus 1,25D decreased proliferation and migration at doses where silibinin alone had no effect. These findings demonstrate that this combination may present a novel approach to target CRC in conditions of chronic colonic inflammation.
authors.affiliation: Department of Pharmacology and Toxicology, The University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA.
authors.forename: Vandanajay
authors.initials: V
authors.lastname: Bhatia
authors.affiliation: Department of Pharmacology and Toxicology, The University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA; Sealy Center for Cancer Cell Biology, The University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA. Electronic address: mfalzon@utmb.edu.
authors.forename: Miriam
authors.initials: M
authors.lastname: Falzon
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004357:Drug Synergism; D019073:HT29 Cells; D006801:Humans; D018167:Receptors, Calcitriol / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000378:metabolism; D000077385:Silybin; D012838:Silymarin / Q000008:administration & dosage / Q000494:pharmacology*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014807:Vitamin D / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D018167:Receptors, Calcitriol; D047490:Retinoid X Receptor alpha; C000604407:SNAI1 protein, human; D012838:Silymarin; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C579457:VDR protein, human; D014807:Vitamin D; D000077385:Silybin; C097949:1,25-dihydroxyvitamin D
keywords: Colon cancer; Inflammation; Snail1; Snail2; Vitamin D receptor
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