title: Different affinity of nuclear factor-kappa B proteins to DNA modified by antitumor cisplatin and its clinically ineffective trans isomer.
abstract: Nuclear factor-kappa B (NF-кB) comprises a family of protein transcription factors that have a regulatory function in numerous cellular processes and are implicated in the cancer cell response to antineoplastic drugs, including cisplatin. We characterized the effects of DNA adducts of cisplatin and ineffective transplatin on the affinity of NF-кB proteins to their consensus DNA sequence (кB site). Although the кB site-NF-κB protein interaction was significantly perturbed by DNA adducts of cisplatin, transplatin adducts were markedly less effective both in cell-free media and in cellulo using a decoy strategy derivatized-approach. Moreover, NF-κB inhibitor JSH-23 [4-methyl-N¹-(3-phenylpropyl)benzene-1,2-diamine] augmented cisplatin cytotoxicity in ovarian cancer cells and the data showed strong synergy with JSH-23 for cisplatin. The distinctive structural features of DNA adducts of the two platinum complexes suggest a unique role for conformational distortions induced in DNA by the adducts of cisplatin with respect to inhibition of the binding of NF-кB to the platinated кB sites. Because thousands of κB sites are present in the DNA, the mechanisms underlying the antitumor efficiency of cisplatin in some tumor cells may involve downstream processes after inhibition of the binding of NF-κB to κB site(s) by DNA adducts of cisplatin, including enhanced programmed cell death in response to drug treatment.
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Kasparkova
authors.affiliation: Centre de Biophysique Moléculaire, CNRS, Orléans, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Thibault
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Kostrhunova
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Stepankova
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno, Czech Republic.
authors.forename: Marie
authors.initials: M
authors.lastname: Vojtiskova
authors.affiliation: Department of Biophysics, Centre of the Region Hana for Biotechnological and Agricultural Research, Faculty of Science, Palacky University in Olomouc, Czech Republic.
authors.forename: Tereza
authors.initials: T
authors.lastname: Muchova
authors.affiliation: Centre de Biophysique Moléculaire, CNRS, Orléans, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Midoux
authors.affiliation: Centre de Biophysique Moléculaire, CNRS, Orléans, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Malinge
authors.affiliation: Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno, Czech Republic.
authors.forename: Viktor
authors.initials: V
authors.lastname: Brabec
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D016384:Consensus Sequence; D018736:DNA Adducts / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D009690:Nucleic Acid Conformation; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D010655:Phenylenediamines / Q000008:administration & dosage / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: C549066:4-methyl-N1-(3-phenylpropyl)benzene-1,2-diamine; D000970:Antineoplastic Agents; D018736:DNA Adducts; D004273:DNA, Neoplasm; D016328:NF-kappa B; D010655:Phenylenediamines; C034697:transplatin; D002945:Cisplatin
keywords: DNA; NF-кB; antitumor activity; cisplatin; modified-oligodeoxynucleotide decoy strategy