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Photodamaging of Mitochondrial DNA to Overcome Cisplatin Resistance by a Ru II –Pt II Bimetallic Complex
Author(s) -
Zheng Yue,
Zhang DongYang,
Zhang Hang,
Cao JianJun,
Tan CaiPing,
Ji LiangNian,
Mao ZongWan
Publication year - 2018
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201803630
Subject(s) - mitochondrial dna , mitochondrion , cisplatin , apoptosis , microbiology and biotechnology , bimetallic strip , dna , chemistry , in vivo , gene , dna damage , irradiation , biology , biophysics , genetics , metal , biochemistry , physics , organic chemistry , chemotherapy , nuclear physics
Abstract Emerging studies have shown that mitochondrial DNA (mtDNA) is an attractive target for anticancer therapeutics. Herein, a heterobimetallic complex [Ru(dip) 2 (μ‐bpm)PtCl 2 ]Cl 2 ( RuPt ; dip=4,7‐diphenyl‐1,10‐phenanthroline; bpm=2,2′‐bipyrimidine) and the corresponding mononuclear complex [Ru(dip) 2 (bpm)]Cl 2 ( Ru ) have been designed and synthesized. RuPt can bind to mtDNA and damage it both in the dark and upon visible light irradiation. By using a variety of methods, it was demonstrated that RuPt can interfere with the function of mtDNA by decreasing the amplification and copy number of mtDNA, and affecting the transcriptional level of mitochondria‐encoded genes. Furthermore, RuPt can disturb the physiological processes of mitochondria and induce caspase‐dependent apoptosis in the presence of light. In addition, RuPt shows low systemic toxicity and potent in vivo anticancer potency upon light irradiation. This study provides strong evidence that mtDNA is an important molecular target of RuPt , and photodamaging mtDNA is an effective strategy to overcome cisplatin resistance.