Energetics, conformation, and recognition of DNA duplexes containing a major adduct of an anticancer azolato-bridged dinuclear PtII complex

• Published in: Biochimica et biophysica acta. General subjects Vol. 1820; no. 10; pp. 1502 - 1511
• Main Authors: Mlcouskova, Jarmila, Malina, Jaroslav, Novohradsky, Vojtech, Kasparkova, Jana, Komeda, Seiji, Brabec, Viktor
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.10.2012
• Subjects: ammonia; Anticancer; cisplatin; crosslinking; Damaged-DNA binding protein; Dinuclear platinum; DNA adducts; DNA conformation; DNA repair; DNA-directed DNA polymerase; neoplasm cells; nucleoproteins; platinum; Thermodynamic stability; thermodynamics; toxicity; dNTP; XPA; HMGB1b; HMGB1a; Polη; FAAS; DNA repair; bp; DSC; EMSA; DNA conformation; Tm; cisplatin; HPLC; Dinuclear platinum; HMG; SDS; AMPZ; CL; Thermodynamic stability; DMS; Damaged-DNA binding protein; rb; CT; PAA; LD; NER; Anticancer
• ISSN: 0304-4165; 1872-8006
• DOI: 10.1016/j.bbagen.2012.05.014

The design of anticancer metallodrugs is currently focused on platinum complexes which form on DNA major adducts that cannot readily be removed by DNA repair systems. Hence, antitumor azolato-bridged dinuclear PtII complexes, such as [{cis-Pt(NH3)2}2(μ‐OH)(μ-pyrazolate)]2+ (AMPZ), have been designed and synthesized. These complexes exhibit markedly higher toxic effects in tumor cell lines than mononuclear conventional cisplatin. Biophysical and biochemical aspects of the alterations induced in short DNA duplexes uniquely and site-specifically modified by the major DNA adduct of AMPZ, namely 1,2-GG intrastrand cross-links, were examined. Attention was also paid to conformational distortions induced in DNA by the adducts of AMPZ and cisplatin, associated alterations in the thermodynamic stability of the duplexes, and recognition of these adducts by high-mobility-group (HMG) domain proteins. Chemical probing of DNA conformation, DNA bending studies and translesion synthesis by DNA polymerase across the platinum adduct revealed that the distortion induced in DNA by the major adduct of AMPZ was significantly less pronounced than that induced by similar cross-links from cisplatin. Concomitantly, the cross-link from AMPZ reduced the thermodynamic stability of the modified duplex considerably less. In addition, HMGB1 protein recognizes major DNA adducts of AMPZ markedly less than those of cisplatin. The experimental evidence demonstrates why the major DNA adducts of the new anticancer azolato-bridged dinuclear PtII complexes are poor substrates for DNA repair observed in a previously published report. The relative resistance to DNA repair explains why these platinum complexes show major pharmacological advantages over cisplatin in tumor cells. [Display omitted] ► Mechanism of anticancer effects of anticancer dinuclear PtII complex was examined. ► The new PtII complex distorts DNA less extensively than conventional cisplatin. ► The new complex thermodynamically destabilizes DNA much less than cisplatin. ► Rationale behind improved antitumor effects of the new PtII complex is outlined.