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Platinated Nucleotides are Substrates for the Human Mitochondrial Deoxynucleotide Carrier (DNC) and DNA Polymerase γ: Relevance for the Development of New Platinum‐Based Drugs.
Author(s) -
Lunetti Paola,
Romano Alessandro,
Carrisi Chiara,
Antonucci Daniela,
Verri Tiziano,
De Benedetto Giuseppe E.,
Dolce Vincenza,
Fanizzi Francesco P.,
Benedetti Michele,
Capobianco Loredana
Publication year - 2016
Publication title -
chemistryselect
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.437
H-Index - 34
ISSN - 2365-6549
DOI - 10.1002/slct.201600961
Subject(s) - cisplatin , nucleotide , dna , mitochondrial dna , mechanism of action , mitochondrion , dna polymerase , biology , polymerase , biochemistry , chemistry , microbiology and biotechnology , genetics , in vitro , gene , chemotherapy
cis‐[PtCl 2 (NH 3 ) 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)( N7 ‐5’‐dGTP)] is incorporated in the mitochondrial DNA by DNA polymerase γ. These results may have critical implications in the development of new generations of anticancer and/or antiviral nucleotide analogues with more specific cellular targets and fewer side effects.