title: Exploring binding affinity of oxaliplatin and carboplatin, to nucleoprotein structure of chromatin: spectroscopic study and histone proteins as a target.
abstract: Platinum drugs are potent chemotherapeutic agents widely used in cancer therapy. They exert their biological activity by binding to DNA, producing DNA adducts; however, in the cell nucleus, DNA is complexed with histone proteins into a nucleoprotein structure known as chromatin. The aim of this study was to explore the binding affinity of oxaliplatin and carboplatin to chromatin using spectroscopic as well as thermal denaturation and equilibrium dialysis techniques. The results showed that the drugs quenched with chromophores of chromatin and the quenching effect for oxaliplatin (Ksv = 3.156) was higher than carboplatin (Ksv = 0.28). The binding of the drugs exhibited hypochromicity both in thermal denaturation profiles and UV absorbance at 210 nm. The binding was positive cooperation with spontaneous reaction and oxaliplatin (Ka = 5.3 × 10(3) M(-1), n = 1.7) exhibited higher binding constant and number of binding sites than carboplatin (Ka = 0.33 × 10(3) M(-1), n = 1.0) upon binding to chromatin. Also secondary structure of chromatin proteins was altered upon drugs binding. It is concluded that oxaliplatin represents higher binding affinity to chromatin compared to carboplatin. In chromatin where DNA is compacted into nucleosomes structure with histones, the affinity of the platinated drugs is reduced and histone proteins may play a fundamental role in this binding process.
authors.affiliation: Department of Biochemistry, Institute of Biochemistry and Biophysics, University of Tehran, P.O. Box 13145-1384, Tehran, Iran.
authors.forename: Hosna
authors.initials: H
authors.lastname: Soori
authors.affiliation: Department of Biochemistry, Institute of Biochemistry and Biophysics, University of Tehran, P.O. Box 13145-1384, Tehran, Iran. Electronic address: arabbani@ut.ac.ir.
authors.forename: Azra
authors.initials: A
authors.lastname: Rabbani-Chadegani
authors.affiliation: Department of Biochemistry, Institute of Biochemistry and Biophysics, University of Tehran, P.O. Box 13145-1384, Tehran, Iran.
authors.forename: Jamshid
authors.initials: J
authors.lastname: Davoodi
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D016190:Carboplatin / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D002843:Chromatin / Q000737:chemistry* / Q000378:metabolism*; D002942:Circular Dichroism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006657:Histones / Q000378:metabolism*; D008297:Male; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000077150:Oxaliplatin; D011485:Protein Binding; D051381:Rats; D013050:Spectrometry, Fluorescence; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D013696:Temperature
chemical_list: D002843:Chromatin; D006657:Histones; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D016190:Carboplatin
keywords: Carboplatin; Chromatin; Histones; Oxaliplatin; Platin-based drugs; Spectroscopy