title: Tris (dibenzylideneacetone) dipalladium, a N-myristoyltransferase-1 inhibitor, is effective against melanoma growth in vitro and in vivo.
abstract: OBJECTIVE
  Melanoma is a solid tumor that is notoriously resistant to chemotherapy, and its incidence is rapidly increasing. Recently, several signaling pathways have been shown to contribute to melanoma tumorigenesis, including constitutive activation of mitogen-activated protein kinase, Akt, and Stat-3. The activation of multiple pathways may account in part for the difficulty in treatment of melanoma. In a recent screen of compounds, we found that an organopalladium compound, Tris (dibenzylideneacetone) dipalladium (Tris DBA), showed significant antiproliferative activity against melanoma cells. Studies were carried out to determine the mechanism of action of Tris DBA.
  
  
  METHODS
  Tris DBA was tested on efficacy on proliferation of human and murine melanoma cells. To find the mechanism of action of Tris DBA, we did Western blot and gene array analyses. The ability of Tris DBA to block tumor growth in vivo was assessed.
  
  
  RESULTS
  Tris DBA has activity against B16 murine and A375 human melanoma in vivo. Tris DBA inhibits several signaling pathways including activation of mitogen-activated protein kinase, Akt, Stat-3, and S6 kinase activation, suggesting an upstream target. Tris DBA was found to be a potent inhibitor of N-myristoyltransferase-1, which is required for optimal activity of membrane-based signaling molecules. Tris DBA showed potent antitumor activity in vivo against melanoma.
  
  
  CONCLUSIONS
  Tris DBA is thus a novel inhibitor of N-myristoyltransferase-1 with significant antitumor activity and is well tolerated in vivo. Further preclinical evaluation of Tris DBA and related complexes is warranted.
authors.affiliation: Department of Dermatology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Sulochana S
authors.initials: SS
authors.lastname: Bhandarkar
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Bromberg
authors.forename: Carol
authors.initials: C
authors.lastname: Carrillo
authors.forename: Ponniah
authors.initials: P
authors.lastname: Selvakumar
authors.forename: Rajendra K
authors.initials: RK
authors.lastname: Sharma
authors.forename: Betsy N
authors.initials: BN
authors.lastname: Perry
authors.forename: Baskaran
authors.initials: B
authors.lastname: Govindarajan
authors.forename: Levi
authors.initials: L
authors.lastname: Fried
authors.forename: Allie
authors.initials: A
authors.lastname: Sohn
authors.forename: Kalpana
authors.initials: K
authors.lastname: Reddy
authors.forename: Jack L
authors.initials: JL
authors.lastname: Arbiser
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008545:Melanoma / Q000188:drug therapy*; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009942:Organometallic Compounds / Q000494:pharmacology; D010165:Palladium / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; C532099:tris(dibenzylideneacetone)dipalladium; D010165:Palladium; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase
references.citation: Cancer Invest. 2005;23(4):303-8
references.pmid: 16100942
references.citation: Bioorg Med Chem Lett. 2003 Jan 6;13(1):115-7
references.pmid: 12467629
references.citation: Clin Cancer Res. 2006 Apr 1;12(7 Pt 2):2301s-2307s
references.pmid: 16609049
references.citation: Mol Med. 1998 Jun;4(6):376-83
references.pmid: 10780880
references.citation: Cancer Treat Rep. 1979 Nov-Dec;63(11-12):2009-10
references.pmid: 393386
references.citation: Clin Cancer Res. 2002 Dec;8(12):3728-33
references.pmid: 12473582
references.citation: Cytokines Cell Mol Ther. 2000 Mar;6(1):9-17
references.pmid: 10976534
references.citation: Proc Natl Acad Sci U S A. 2005 Jan 4;102(1):175-9
references.pmid: 15611471
references.citation: J Immunol. 2005 Apr 1;174(7):3925-31
references.pmid: 15778348
references.citation: Semin Cancer Biol. 2004 Apr;14(2):81-91
references.pmid: 15018892
references.citation: J Immunother. 2006 Jul-Aug;29(4):455-63
references.pmid: 16799341
references.citation: Cancer Res. 1997 Jul 15;57(14):3032-9
references.pmid: 9230219
references.citation: Clin Cancer Res. 2006 Apr 1;12(7 Pt 2):2353s-2358s
references.pmid: 16609058
references.citation: Mol Med. 2002 Dec;8(12):877-84
references.pmid: 12606824
references.citation: Nat Genet. 2003 Jan;33(1):19-20
references.pmid: 12447372
references.citation: J Biol Chem. 2003 Sep 12;278(37):35501-7
references.pmid: 12816951
references.citation: Anal Biochem. 1991 Dec;199(2):149-53
references.pmid: 1725948
references.citation: Br J Cancer. 2006 Sep 4;95(5):581-6
references.pmid: 16880785
references.citation: J Am Acad Dermatol. 1999 Jun;40(6 Pt 1):925-9
references.pmid: 10365923
references.citation: Cancer Res. 2002 Jul 1;62(13):3868-75
references.pmid: 12097302
references.citation: J Clin Oncol. 2005 Sep 1;23(25):6107-16
references.pmid: 16135477
references.citation: J Biol Chem. 2003 Mar 14;278(11):9790-5
references.pmid: 12514183
references.citation: Cancer Res. 2002 Dec 15;62(24):7335-42
references.pmid: 12499277
references.citation: Cancer Res. 2001 Oct 1;61(19):7318-24
references.pmid: 11585772
references.citation: Proc Natl Acad Sci U S A. 1997 Feb 4;94(3):861-6
references.pmid: 9023347
references.citation: Cancer Res. 2006 Jan 15;66(2):613-21
references.pmid: 16423986
references.citation: Cell Death Differ. 2004 Oct;11(10):1084-91
references.pmid: 15243584
references.citation: Cancer Res. 2005 Mar 15;65(6):2412-21
references.pmid: 15781657
references.citation: Semin Oncol. 1997 Feb;24(1 Suppl 4):S39-43
references.pmid: 9122733
references.citation: Cancer Res. 2004 Nov 15;64(22):8222-30
references.pmid: 15548688
references.citation: Cancer Cell. 2003 Aug;4(2):95-8
references.pmid: 12957284
references.citation: J Immunol. 1998 Feb 1;160(3):1224-32
references.pmid: 9570538
references.citation: J Biol Chem. 2002 Mar 8;277(10):7920-8
references.pmid: 11773061
references.citation: Protein Expr Purif. 1996 Jun;7(4):431-7
references.pmid: 8776763
references.citation: Cancer. 2005 Sep 1;104(5):1045-8
references.pmid: 16007689
references.citation: Oncogene. 1998 Jul 2;16(26):3397-402
references.pmid: 9692547
references.citation: J Clin Invest. 2002 May;109(9):1139-42
references.pmid: 11994401
references.citation: Blood. 2006 Mar 15;107(6):2409-14
references.pmid: 16304057
references.citation: Cancer Cell. 2002 Jul;2(1):5-7
references.pmid: 12150818
references.citation: Nat Med. 1996 Oct;2(10):1096-103
references.pmid: 8837607
references.citation: Cell Death Differ. 2006 Feb;13(2):352-3
references.pmid: 16110320
references.citation: Cancer Res. 1997 Dec 1;57(23):5221-5
references.pmid: 9393738
references.citation: J Cancer Res Clin Oncol. 1999;125(5):292-6
references.pmid: 10359134
references.citation: Cancer. 2005 Jun 15;103(12):2584-9
references.pmid: 15887220
references.citation: Biochem J. 1993 Apr 15;291 ( Pt 2):635-9
references.pmid: 8484742
references.citation: Curr Biol. 2004 Jul 27;14(14):1296-302
references.pmid: 15268862