Platinated Nucleotides are Substrates for the Human Mitochondrial Deoxynucleotide Carrier (DNC) and DNA Polymerase Upsilon: Relevance for the Development of New Platinum-Based Drugs

摘要

abstract_textpcis-PtCl2(NH3)(2) (cisplatin) is among the highest effective antitumor drugs used for the chemotherapeutic treatment of a broad range of malignancies. Recently, alongside with the classical direct bond to DNA, an alternative mechanism of action mediated by N7 platinated nucleotides has been suggested for cisplatin. Considering that mitochondria play an important role in cell death activation and in a significant portion of the clinical activity and pharmacological properties associated with cisplatin, aim of this research was to evaluate the possibility that platinated deoxynucleotides, as the model complex Pt(dien) (N7-5'-dGTP) (1), dien= diethylenetriamine, could be transported into mitochondria and then incorporated into mtDNA. The kinetic characterization has revealed that the mitochondrial deoxynucleotide carrier (DNC) transports complex 1 with high affinity. Finally, a highly efficient in organello DNA synthesis system, followed by ICP-AES, has demonstrated that Pt(dien) (N75'- dGTP) is incorporated in the mitochondrial DNA by DNA polymerase Upsilon. These results may have critical implications in the development of new generations of anticancer and/or anti-viral nucleotide analogues with more specific cellular targets and fewer side effects./p/abstract_text