Abstract
Nuclear DNA is the target responsible for anticancer activity of platinum anticancer drugs. Their activity is mediated by altered signals related to programmed cell death and the activation of various signaling pathways. An example is activation of nuclear factor kappaB (NF-κB). Binding of NF-κB proteins to their consensus sequences in DNA (κB sites) is the key biochemical activity responsible for the biological functions of NF-κB. Using gel-mobility-shift assays and surface plasmon resonance spectroscopy we examined the interactions of NF-κB proteins with oligodeoxyribonucleotide duplexes containing κB site damaged by DNA adducts of three platinum complexes. These complexes markedly differed in their toxic effects in tumor cells and comprised highly cytotoxic trinuclear platinum(II) complex BBR3464, less cytotoxic conventional cisplatin and ineffective transplatin. The results indicate that structurally different DNA adducts of these platinum complexes exhibit a different efficiency to affect the affinity of the platinated DNA (κB sites) to NF-κB proteins. Our results support the hypothesis that structural perturbations induced in DNA by platinum(II) complexes correlate with their higher efficiency to inhibit binding of NF-κB proteins to their κB sites and cytotoxicity as well. However, the full generalization of this hypothesis will require to evaluate a larger series of platinum(II) complexes.
Highlights
IntroductionCis-Diamminedichloridoplatinum(II) (cisplatin) is one of the most potent antitumor agents in cancer chemotherapy[1]
Cis-Diamminedichloridoplatinum(II) is one of the most potent antitumor agents in cancer chemotherapy[1]
The binding properties of NF-κBreconstituted from purified p50 and p65 proteins and the native complex of NF-κB to DNA containing κB site damaged by DNA adducts of BBR3464 was investigated with the aid of classical electrophoretic mobility shift assay (EMSA) and surface plasmon resonance (SPR) spectroscopy which makes it possible to study such interactions in real time as well
Summary
Cis-Diamminedichloridoplatinum(II) (cisplatin) is one of the most potent antitumor agents in cancer chemotherapy[1]. Thousands of κB sites are present in the natural DNAs11,12 and interestingly, these κB sites conserve the consecutive guanines[13,14] which represent preferential DNA binding sites of antitumor platinum(II) complexes. We used for this study another bifunctional platinum(II) agent with a unique mode of DNA binding, the trinuclear [{trans-PtCl(NH3)2}2(μ-trans-Pt(NH3)2{NH2(CH2)6NH2}2)]4+ (Triplatin, BBR3464) (Fig. 1). This complex is markedly more cytotoxic than cisplatin and its antitumor derivatives used in the clinic[15,16,17] and retains activity against cell lines and tumors resistant to cisplatin in vitro as well as in vivo[18,19]. The binding properties of NF-κBreconstituted from purified p50 and p65 proteins and the native complex of NF-κB to DNA containing κB site damaged by DNA adducts of BBR3464 was investigated with the aid of classical electrophoretic mobility shift assay (EMSA) and surface plasmon resonance (SPR) spectroscopy which makes it possible to study such interactions in real time as well
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