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: Jana Kasparkova, Thomas Thibault, Hana Kostrhunova, Jana Stepankova, Marie Vojtiskova, Tereza Muchova, Patrick Midoux, Jean-Marc Malinge, Viktor Brabec
• Journal: The FEBS journal (FEBS J) Vol. 281 Issue 5 Pg. 1393-1408 (Mar 2014) ISSN: 1742-4658 [Electronic] England
• PMID: 24418212 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 FEBS.

Chemical References

• 4-methyl-N1-(3-phenylpropyl)benzene-1,2-diamine
• Antineoplastic Agents
• DNA Adducts
• DNA, Neoplasm
• NF-kappa B
• Phenylenediamines
• transplatin
• Cisplatin

Topics

• Antineoplastic Agents (administration & dosage, chemistry, pharmacology)
• Base Sequence
• Binding Sites (genetics)
• Cell Line, Tumor
• Cisplatin (administration & dosage, chemistry, pharmacology)
• Consensus Sequence
• DNA Adducts (chemistry, genetics, metabolism)
• DNA, Neoplasm (chemistry, genetics, metabolism)
• Drug Synergism
• Female
• HEK293 Cells
• Humans
• NF-kappa B (antagonists & inhibitors, chemistry, metabolism)
• Nucleic Acid Conformation
• Ovarian Neoplasms (drug therapy, genetics, metabolism)
• Phenylenediamines (administration & dosage, pharmacology)
• Stereoisomerism