title: Targeting of the Akt-nuclear factor-kappa B signaling network by [1-(4-chloro-3-nitrobenzenesulfonyl)-1H-indol-3-yl]-methanol (OSU-A9), a novel indole-3-carbinol derivative, in a mouse model of hepatocellular carcinoma.
abstract: Constitutive activation of Akt and nuclear factor-kappaB (NF-kappaB) represents major cellular abnormalities associated with the development and progression of hepatocellular carcinoma (HCC). Based on the structure of indole-3-carbinol, a chemopreventive phytochemical, we developed a novel derivative, [1-(4-chloro-3-nitrobenzenesulfonyl)-1H-indol-3-yl]-methanol (OSU-A9), that exhibits higher potency in inducing apoptosis by targeting the Akt-NF-kappaB signaling network. This study was aimed at assessing the antitumor activity of OSU-A9 using both in vitro and in vivo models of HCC, a malignancy in which the Akt-NF-kappaB signaling network plays major roles in pathogenesis and therapeutic resistance. Our data show that OSU-A9 was 100 times more potent than indole-3-carbinol in suppressing the viability of Hep3B, Huh7, and PLC5 HCC cells with IC(50) values ranging from 2.8 to 3.2 microM. OSU-A9 interfered with the interplay between Akt- and NF-kappaB-mediated oncogenic signaling, leading to changes in the functional status of diverse signaling effectors involved in cell cycle progression, apoptosis, angiogenesis, and metastasis. The in vivo efficacy of OSU-A9 was assessed in nude mice bearing luciferase-expressing Hep3B xenograft tumors. Daily oral treatments with OSU-A9 at 25 or 50 mg/kg for 56 days suppressed tumor growth by 67 and 80%, respectively, which was correlated with changes in intratumoral biomarkers pertinent to Akt-NF-kappaB signaling, and without apparent toxicity or evidence of hepatic biotransformation enzyme induction. Together, these findings indicate that OSU-A9 is a potent, orally bioavailable inhibitor of the Akt-NF-kappaB signaling network with a broad spectrum of antitumor activity that includes targets regulating multiple aspects of HCC pathogenesis and progression.
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Hany A
authors.initials: HA
authors.lastname: Omar
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Sargeant
authors.forename: Jing-Ru
authors.initials: JR
authors.lastname: Weng
authors.forename: Dasheng
authors.initials: D
authors.lastname: Wang
authors.forename: Samuel K
authors.initials: SK
authors.lastname: Kulp
authors.forename: Tushar
authors.initials: T
authors.lastname: Patel
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000432:Methanol / Q000008:administration & dosage / Q000031:analogs & derivatives*; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: C523234:(1-(4-chloro-3-nitrobenzenesulfonyl)-1H-indol-3-yl)-methanol; D007211:Indoles; D016328:NF-kappa B; C016517:indole-3-carbinol; D051057:Proto-Oncogene Proteins c-akt; D000432:Methanol
references.citation: Hepatology. 2002 Dec;36(6):1528-36
references.pmid: 12447879
references.citation: Mol Imaging. 2007 Sep-Oct;6(5):315-22
references.pmid: 18092516
references.citation: Cancer Res. 2008 Aug 15;68(16):6698-707
references.pmid: 18701494
references.citation: Prostate. 2004 May 15;59(3):292-303
references.pmid: 15042605
references.citation: Cancer Res. 2008 May 15;68(10):3999-4009
references.pmid: 18483287
references.citation: J Gastroenterol. 2006 Feb;41(2):166-76
references.pmid: 16568376
references.citation: Cancer. 2002 Oct 15;95(8):1696-705
references.pmid: 12365017
references.citation: Annu Rev Pharmacol Toxicol. 1991;31:253-87
references.pmid: 2064376
references.citation: Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8847-51
references.pmid: 9671767
references.citation: Gastroenterology. 2007 Jun;132(7):2557-76
references.pmid: 17570226
references.citation: Cancer Res. 2007 Aug 15;67(16):7815-24
references.pmid: 17699787
references.citation: EMBO J. 2000 Nov 1;19(21):5720-8
references.pmid: 11060023
references.citation: Neoplasia. 2000 Nov-Dec;2(6):491-5
references.pmid: 11228541
references.citation: Nat Rev Cancer. 2002 Oct;2(10):764-76
references.pmid: 12360279
references.citation: Cancer. 2003 Apr 15;97(8):1929-40
references.pmid: 12673720
references.citation: Br J Cancer. 2006 Jul 17;95(2):210-7
references.pmid: 16819541
references.citation: Clin Cancer Res. 2002 Apr;8(4):1228-36
references.pmid: 11948137
references.citation: J Biol Chem. 2006 Oct 20;281(42):31770-7
references.pmid: 16940298
references.citation: Cancer Lett. 2005 Nov 18;229(2):157-69
references.pmid: 16125305
references.citation: Clin Cancer Res. 2006 Sep 1;12(17):5199-206
references.pmid: 16951239
references.citation: Mol Cell Biol. 1999 Nov;19(11):7420-7
references.pmid: 10523630
references.citation: Clin Exp Metastasis. 2003;20(8):745-56
references.pmid: 14713108
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19750-5
references.pmid: 19064917
references.citation: Cancer. 2005 Jan 15;103(2):307-12
references.pmid: 15593087
references.citation: Int J Oncol. 2002 Sep;21(3):515-9
references.pmid: 12168094
references.citation: Mol Carcinog. 2006 Jun;45(6):355-61
references.pmid: 16673382
references.citation: Hepatology. 2009 Jan;49(1):332-4
references.pmid: 19115217
references.citation: Nat Rev Immunol. 2005 Oct;5(10):749-59
references.pmid: 16175180
references.citation: EMBO J. 2001 May 1;20(9):2160-70
references.pmid: 11331582
references.citation: Cell. 2002 May 3;109(3):321-34
references.pmid: 12015982
references.citation: Carcinogenesis. 2004 Nov;25(11):2257-64
references.pmid: 15240508
references.citation: Cancer Res. 2000 Oct 1;60(19):5390-4
references.pmid: 11034077
references.citation: Nat Rev Cancer. 2004 Jul;4(7):540-50
references.pmid: 15229479
references.citation: World J Gastroenterol. 2005 Dec 21;11(47):7391-400
references.pmid: 16437707
references.citation: Cancer Res. 2008 Feb 15;68(4):1204-12
references.pmid: 18281497
references.citation: Toxicol Appl Pharmacol. 2006 Mar 1;211(2):115-23
references.pmid: 16043203
references.citation: Cancer Lett. 2008 Apr 18;262(2):153-63
references.pmid: 18314259
references.citation: Exp Cell Res. 2004 Nov 1;300(2):427-39
references.pmid: 15475007
references.citation: Clin Exp Metastasis. 2003;20(8):733-44
references.pmid: 14713107
references.citation: Hepatology. 2001 Jul;34(1):55-61
references.pmid: 11431734
references.citation: Nutr Cancer. 2004;48(1):84-94
references.pmid: 15203382
references.citation: Toxicol Pathol. 2007 Jun;35(4):549-61
references.pmid: 17562488
references.citation: Cancer Res. 2005 Feb 1;65(3):967-71
references.pmid: 15705897