title: Resveratrol enhances the sensitivity of cholangiocarcinoma to chemotherapeutic agents.
abstract: Cholangiocarcinomas are devastating cancers that are resistant to chemotherapies. Resveratrol, a food-derived polyphenol with antitumorigenic properties, can regulate the expression of cytochrome p450 1b1 (Cyp1b1), which may confer chemoresistance in various cancers. Our aims were to assess the effects of resveratrol on the sensitivity of cholangiocarcinoma cells to chemotherapeutic agents and show an association between Cyp1b1 expression and chemosensitivity. Cholangiocarcinoma cell lines were treated with resveratrol before the addition of 5-fluorouracil (5-FU), gemcitabine, or mitomycin C. Cell proliferation and apoptosis were assessed by MTS assays and Annexin staining. Resveratrol effects on cholangiocarcinoma tumor sensitivity to 5-FU was assessed in an in vivo xenograft model using Mz-ChA-1 cells. After resveratrol treatment, Cyp1b1 expression was assessed by real-time PCR and immunoblotting. Stable-transfected cell lines with Cyp1b1 expression knocked down (Mz-Cyp1b1) were used to assess sensitivity to chemotherapeutic agents by MTS assays and Annexin staining and in a xenograft model using Mz-ChA-1 and Mz-Cyp1b1 cells, respectively. For each chemotherapeutic agent, co-treatment with resveratrol in vitro decreased cell proliferation and increased apoptosis to a greater extent than with the chemotherapeutic agent alone. In vivo, 5-FU+resveratrol decreased tumor size and increased TUNEL staining to a greater extent than 5-FU alone. In parallel, resveratrol decreased Cyp1b1 expression in Mz-ChA-1 cells and in cholangiocarcinoma tumors. Mz-Cyp1b1 cells were more sensitive to chemotherapeutic agents in vitro than mock-transfected cells, and Mz-Cyp1b1-induced tumors were more susceptible to 5-FU treatment. We suggest that resveratrol treatment may be a useful adjunct therapy to improve chemosensitivity in cholangiocarcinoma.
authors.affiliation: Department of Internal Medicine, Texas A&M Health Science Center, College of Medicine, Temple, TX, USA.
authors.forename: Gabriel A
authors.initials: GA
authors.lastname: Frampton
authors.forename: Eric A
authors.initials: EA
authors.lastname: Lazcano
authors.forename: Huang
authors.initials: H
authors.lastname: Li
authors.forename: Akimuddin
authors.initials: A
authors.lastname: Mohamad
authors.forename: Sharon
authors.initials: S
authors.lastname: DeMorrow
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D003577:Cytochrome P-450 Enzyme System / Q000494:pharmacology; D003841:Deoxycytidine / Q000031:analogs & derivatives; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D016685:Mitomycin / Q000494:pharmacology / Q000627:therapeutic use; D000077185:Resveratrol; D013267:Stilbenes; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D013267:Stilbenes; D003841:Deoxycytidine; D016685:Mitomycin; D003577:Cytochrome P-450 Enzyme System; D000077185:Resveratrol; D005472:Fluorouracil; D000093542:Gemcitabine
references.citation: In Vitro Cell Dev Biol. 1989 Jun;25(6):503-10
references.pmid: 2544546
references.citation: Clin Liver Dis. 2008 Feb;12(1):131-50, ix
references.pmid: 18242501
references.citation: Int J Radiat Oncol Biol Phys. 2009 May 1;74(1):219-28
references.pmid: 19362240
references.citation: J Hepatol. 2007 Feb;46(2):222-9
references.pmid: 17069924
references.citation: Phytother Res. 2009 Feb;23(2):226-30
references.pmid: 18726924
references.citation: Hepatology. 2003 May;37(5):961-9
references.pmid: 12717374
references.citation: Pancreatology. 2008;8(6):566-76
references.pmid: 18824880
references.citation: J Androl. 2007 Mar-Apr;28(2):282-93
references.pmid: 17050787
references.citation: J Biol Chem. 2007 Apr 27;282(17):13098-113
references.pmid: 17329257
references.citation: J Biol Chem. 2007 Jul 6;282(27):19385-98
references.pmid: 17513867
references.citation: J Clin Gastroenterol. 2007 Nov-Dec;41(10):894-900
references.pmid: 18090157
references.citation: Mol Nutr Food Res. 2007 May;51(5):517-24
references.pmid: 17440990
references.citation: Cancer. 2009 Aug 15;115(16):3738-48
references.pmid: 19514085
references.citation: J Hepatol. 1985;1(6):579-96
references.pmid: 4056357
references.citation: Biomed Pharmacother. 2008 Nov;62(9):622-9
references.pmid: 18804944
references.citation: Drug Metab Dispos. 1997 May;25(5):617-22
references.pmid: 9152602
references.citation: Cancer Res. 2004 May 15;64(10):3517-24
references.pmid: 15150106
references.citation: Neurosci Lett. 2004 Jun 17;363(3):257-61
references.pmid: 15182955
references.citation: Int J Cancer. 2004 Mar 20;109(2):182-8
references.pmid: 14750167
references.citation: Oncogene. 2004 Dec 9;23(57):9247-58
references.pmid: 15489888
references.citation: Genes Chromosomes Cancer. 1990 Nov;2(4):300-10
references.pmid: 2176543
references.citation: Int J Cancer. 2009 Aug 1;125(3):565-76
references.pmid: 19358267
references.citation: Cancer Res. 2009 Sep 1;69(17):7038-45
references.pmid: 19690133
references.citation: Am J Physiol. 1994 Jun;266(6 Pt 1):G1060-70
references.pmid: 8023938
references.citation: Int J Mol Med. 2006 Jun;17(6):1069-75
references.pmid: 16685418
references.citation: J Hepatol. 2008 Aug;49(2):160-2
references.pmid: 18538440
references.citation: Infect Disord Drug Targets. 2009 Aug;9(4):400-14
references.pmid: 19689382
references.citation: Cancer Res. 1997 Jul 15;57(14):3026-31
references.pmid: 9230218
references.citation: Anticancer Res. 2009 Feb;29(2):509-15
references.pmid: 19331196
references.citation: Toxicol Lett. 2010 Feb 1;192(2):221-8
references.pmid: 19879933
references.citation: Liver Int. 2009 May;29(5):670-7
references.pmid: 19226332
references.citation: Mol Cancer Ther. 2006 Aug;5(8):2034-42
references.pmid: 16928824
references.citation: Cancer Res. 2005 Dec 15;65(24):11437-46
references.pmid: 16357152
references.citation: Oncogene. 2004 Nov 25;23(55):8979-86
references.pmid: 15480430
references.citation: Int J Cancer. 2010 May 1;126(9):2112-22
references.pmid: 19795457
references.citation: Br J Cancer. 2001 Jul 20;85(2):242-6
references.pmid: 11461084
references.citation: Carcinogenesis. 1999 Aug;20(8):1607-13
references.pmid: 10426814
references.citation: Drug Metab Dispos. 2002 Nov;30(11):1149-52
references.pmid: 12386117
references.citation: Int J Cancer. 2002 Apr 10;98(5):761-9
references.pmid: 11920648
references.citation: Biochem Pharmacol. 2001 Jul 15;62(2):207-12
references.pmid: 11389879
references.citation: Carcinogenesis. 2004 Oct;25(10):2005-13
references.pmid: 15142886
references.citation: Int J Cancer. 1992 Sep 9;52(2):252-60
references.pmid: 1355757
references.citation: Cancer Res. 2002 Sep 1;62(17):4945-54
references.pmid: 12208745
references.citation: Am J Physiol Gastrointest Liver Physiol. 2008 Dec;295(6):G1150-8
references.pmid: 18832445
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: Prostaglandins Leukot Essent Fatty Acids. 2005 Mar;72(3):219-26
references.pmid: 15664307
references.citation: J Biol Chem. 2003 Oct 17;278(42):41482-90
references.pmid: 12902349
references.citation: Carcinogenesis. 2002 Sep;23(9):1531-6
references.pmid: 12189197
references.citation: Annu Rev Pharmacol Toxicol. 2001;41:297-316
references.pmid: 11264459
references.citation: J Pharmacol Exp Ther. 2001 Feb;296(2):537-41
references.pmid: 11160641
references.citation: J Natl Cancer Inst Monogr. 2000;(27):95-112
references.pmid: 10963622
references.citation: Hepatology. 2005 Jan;41(1):5-15
references.pmid: 15690474
references.citation: Liver Int. 2008 Dec;28(10):1426-36
references.pmid: 18397227
references.citation: Science. 1997 Jan 10;275(5297):218-20
references.pmid: 8985016
references.citation: J Med Food. 2007 Jun;10(2):218-24
references.pmid: 17651055