title: Inhibition of Sp1-dependent transcription and antitumor activity of the new aureolic acid analogues mithramycin SDK and SK in human ovarian cancer xenografts.
abstract: OBJECTIVE
  Increased activity of Sp family of transcription factors is a frequent and critical event in cancer development and progression. Genes governing tumor growth, invasion and angiogenesis are regulated by Sp factors, like Sp1, Sp3 or Sp4, and are frequently over-expressed in tumors. Targeting Sp factors has been explored as a therapeutic approach. Mithramycin (MTM) is a natural antibiotic that binds DNA and inhibit Sp1-dependent transcription. New analogues, named MTM-SDK and MTM-SK, were recently obtained by genetic engineering of the MTM biosynthetic pathway and have demonstrated improved transcriptional and antiproliferative activity in ovarian cancer cell lines in vitro. In the present study we evaluated the activity of the new compounds in human ovarian cancer xenografts.
  
  
  METHODS
  Expression of Sp1 and target proteins in ovarian cancer specimens and tumor xenografts was assessed by immunohistochemistry. Drug-induced silencing of Sp1-regulated genes in cells and tumor xenograft samples was assessed by quantitative RT-PCR. Toxicity and antitumor activity of the compounds were investigated in healthy and tumor-bearing immunocompromised mice, respectively.
  
  
  RESULTS
  Expression of Sp1 was frequently increased in human epithelial ovarian cancers. MTM-SDK and MTM-SK acted as potent inhibitors of Sp1-dependent transcription both in vitro and in tumor xenografts. Both compounds were well tolerated even after prolonged administration and delayed growth of ovarian tumor xenografts. MTM-SDK was particularly effective against orthotopic tumors leading to a significant increase of survival and delay of tumor progression.
  
  
  CONCLUSIONS
  MTM-SDK and MTM-SK show relevant activity in vivo and represent interesting candidates for treatment of ovarian cancers.
authors.affiliation: Laboratory of Molecular Pharmacology, Mario Negri Institute for Pharmacological Research, Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Previdi
authors.forename: Anastasia
authors.initials: A
authors.lastname: Malek
authors.forename: Veronica
authors.initials: V
authors.lastname: Albertini
authors.forename: Cristina
authors.initials: C
authors.lastname: Riva
authors.forename: Carlo
authors.initials: C
authors.lastname: Capella
authors.forename: Massimo
authors.initials: M
authors.lastname: Broggini
authors.forename: Giuseppina M
authors.initials: GM
authors.lastname: Carbone
authors.forename: Jurgen
authors.initials: J
authors.lastname: Rohr
authors.forename: Carlo V
authors.initials: CV
authors.lastname: Catapano
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008926:Plicamycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D016329:Sp1 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D016329:Sp1 Transcription Factor; C520007:mithramycin SK; D008926:Plicamycin
references.citation: Gynecol Oncol. 2007 Sep;106(3):526-37
references.pmid: 17559911
references.citation: J Am Chem Soc. 2003 May 14;125(19):5745-53
references.pmid: 12733914
references.citation: Nucleic Acids Res. 2007;35(7):2215-26
references.pmid: 17369273
references.citation: Cancer Res. 2005 Feb 1;65(3):1007-17
references.pmid: 15705902
references.citation: Cancer Res. 2000 Nov 15;60(22):6531-6
references.pmid: 11103824
references.citation: Biochem Biophys Res Commun. 2006 Jun 23;345(1):292-301
references.pmid: 16678129
references.citation: J Am Chem Soc. 2002 May 29;124(21):6056-62
references.pmid: 12022840
references.citation: Exp Oncol. 2007 Jun;29(2):121-5
references.pmid: 17704744
references.citation: Cancer Cell. 2004 Jan;5(1):19-24
references.pmid: 14749123
references.citation: Cancer Res. 2003 Mar 15;63(6):1235-41
references.pmid: 12649182
references.citation: Int J Gynecol Cancer. 2005 Sep-Oct;15(5):878-83
references.pmid: 16174239
references.citation: Biochemistry. 2003 Jul 15;42(27):8313-24
references.pmid: 12846580
references.citation: J Biol Chem. 2002 Aug 9;277(32):28815-22
references.pmid: 12052832
references.citation: J Clin Invest. 1991 Nov;88(5):1613-21
references.pmid: 1834700
references.citation: J Am Chem Soc. 2002 Feb 27;124(8):1606-14
references.pmid: 11853433
references.citation: Gynecol Oncol. 2009 Nov;115(2):290-301
references.pmid: 19717182
references.citation: Nat Rev Cancer. 2009 Mar;9(3):167-81
references.pmid: 19238149
references.citation: J Natl Cancer Inst. 2006 Jun 21;98(12):855-68
references.pmid: 16788159
references.citation: Eur J Cancer. 2005 Nov;41(16):2438-48
references.pmid: 16209919
references.citation: J Biol Chem. 2006 Jul 28;281(30):21433-21444
references.pmid: 16714763
references.citation: J Biol Chem. 2008 May 16;283(20):13934-42
references.pmid: 18353772
references.citation: Cancer Res. 2005 Aug 15;65(16):7378-85
references.pmid: 16103090
references.citation: Int J Cancer. 2008 Mar 15;122(6):1430-4
references.pmid: 18027851
references.citation: J Am Chem Soc. 2005 Dec 21;127(50):17594-5
references.pmid: 16351075
references.citation: J Clin Oncol. 2006 Feb 20;24(6):988-94
references.pmid: 16461779
references.citation: Mol Cancer Ther. 2006 Nov;5(11):2737-46
references.pmid: 17121920
references.citation: Biochemistry. 1993 Jul 6;32(26):6588-604
references.pmid: 8329387
references.citation: Clin Cancer Res. 2008 May 15;14(10):3030-5
references.pmid: 18483368
references.citation: Nucleic Acids Res. 2006 Mar 29;34(6):1721-34
references.pmid: 16571899
references.citation: Biochemistry. 1991 Apr 30;30(17):4290-7
references.pmid: 1827033
references.citation: Nat Rev Cancer. 2009 Jun;9(6):415-28
references.pmid: 19461667
references.citation: Cancer Res. 2008 Jul 1;68(13):5345-54
references.pmid: 18593936
references.citation: Mol Ther. 2004 Dec;10(6):1032-42
references.pmid: 15564135
references.citation: Cancer Res. 2007 Mar 15;67(6):2816-23
references.pmid: 17363604
references.citation: Cancer Res. 2007 Apr 1;67(7):3286-94
references.pmid: 17409437
references.citation: J Clin Oncol. 2008 Feb 20;26(6):995-1005
references.pmid: 18195328
references.citation: N Engl J Med. 2004 Dec 9;351(24):2519-29
references.pmid: 15590954
references.citation: Appl Microbiol Biotechnol. 2006 Nov;73(1):1-14
references.pmid: 17013601
references.citation: Cancer Biol Ther. 2007 Nov;6(11):1733-42
references.pmid: 17986852
references.citation: Cancer Cell. 2002 Feb;1(1):53-62
references.pmid: 12086888
references.citation: Carcinogenesis. 2009 Jul;30(7):1193-201
references.pmid: 19406933
references.citation: N Engl J Med. 2006 Jan 5;354(1):34-43
references.pmid: 16394300
references.citation: Nat Rev Cancer. 2005 May;5(5):355-66
references.pmid: 15864277