Nuclear condensation and free radical scavenging: a dual mechanism of bisbenzimidazoles to modulate radiation damage to DNA.
The complexing of histones with DNA and the resulting condensation of chromatin protects mammalian cell, from radiation-induced strand breakage. In the present study, benzimidazoles DMA and TBZ showed marked radioprotection through drug-induced compaction of chromatin and direct quenching of free radicals generated by radiation. The mammalian cells were incubated with 100 microM concentration of DMA and TBZ and irradiated at 5 Gy; both the ligands showed nuclei condensation suggesting a probable mechanism to protect DNA from radiation damage. The bisubstituted analogs of Hoechst 33342 are found to be better free radical scavengers and protect DNA against radiation-induced damage at a lower concentration than the parent molecule. Both the ligands also quenched free radicals in isolated free radical system suggesting their dual mode of action against radiation-induced damage to DNA. Molecules binding to the chromatin alter gene expression, whereas in this study both the ligands have not shown any profound effect on the nucleosome assembly and gene expression in vitro and in vivo. Both ligands afford a 2-fold protection by altering DNA structure as well as through direct free radical quenching in bulk solution in comparison to the parent ligand, which acts only through quenching of free radicals.
Tawar
Urmila
U
Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110007, India.
Bansal
Sandhya
S
Shrimal
Shiteshu
S
Singh
Manish
M
Tandon
Vibha
V
D001483:Base Sequence; D001562:Benzimidazoles / Q000494:pharmacology*; D006690:Bisbenzimidazole / Q000494:pharmacology; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects* / Q000528:radiation effects; D020552:Comet Assay; D019610:Cytoprotection / Q000187:drug effects; D004247:DNA / Q000378:metabolism / Q000528:radiation effects*; D004249:DNA Damage / Q000187:drug effects*; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D009707:Nucleosomes / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011829:Radiation Dosage; D011837:Radiation-Protective Agents / Q000494:pharmacology; D014407:Tumor Cells, Cultured
C477188:5-(4-methylpiperazin-1-yl)-2-(2'-(2''-(4-hydroxy-3-methoxyphenyl)-5''-benzimidazolyl)-5'-benzimidazolyl)benzimidazole; C477187:5-(4-methylpiperazin-1-yl)-2-(2'-(3,4-dimethoxyphenyl)-5'-benzimidazolyl)benzimidazole; D001562:Benzimidazoles; D016166:Free Radical Scavengers; D009707:Nucleosomes; D010879:Piperazines; D011837:Radiation-Protective Agents; D004247:DNA; D006690:Bisbenzimidazole