Enhancing Cytotoxicity of a Monofunctional Platinum Complex via a Dual-DNA-Damage Approach

Mitochondrial DNA (mtDNA) is an attractive cellular target for anticancer agents in addition to nuclear DNA (nDNA). The cationic platinum­(II) complex cis-[Pt­(NP)­(NH3)2Cl]­NO3 (PtNP, NP = N-(2-ethylpyridine)-1,8-naphthalimide) bearing the DNA-intercalating moiety NP was designed. The structure of...

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Veröffentlicht in:Inorganic chemistry 2019-10, Vol.58 (19), p.13150-13160
Hauptverfasser: Guo, Yan, He, Yafeng, Wu, Shengde, Zhang, Shuren, Song, Dongfan, Zhu, Zhenzhu, Guo, Zijian, Wang, Xiaoyong
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container_end_page 13160
container_issue 19
container_start_page 13150
container_title Inorganic chemistry
container_volume 58
creator Guo, Yan
He, Yafeng
Wu, Shengde
Zhang, Shuren
Song, Dongfan
Zhu, Zhenzhu
Guo, Zijian
Wang, Xiaoyong
description Mitochondrial DNA (mtDNA) is an attractive cellular target for anticancer agents in addition to nuclear DNA (nDNA). The cationic platinum­(II) complex cis-[Pt­(NP)­(NH3)2Cl]­NO3 (PtNP, NP = N-(2-ethylpyridine)-1,8-naphthalimide) bearing the DNA-intercalating moiety NP was designed. The structure of PtNP was fully characterized by single-crystal X-ray crystallography, NMR, and HRMS. PtNP is superior to cisplatin in both in vitro and in vivo anticancer activities with low systemic toxicity. The interaction of PtNP with CT-DNA demonstrated that PtNP could effectively bind to DNA through both covalent and noncovalent double binding modes. In addition to causing significant damage to nDNA and remarkable inhibition to DNA damage repair, PtNP also distributed in mitochondria, inducing mtDNA damage and affecting the downstream transcriptional level of mitochondrion-encoded genes. In addition, PtNP disturbed the physiological processes of mitochondria by reducing the mitochondrial membrane potential and promoting the generation of reactive oxygen species. Mechanistic studies demonstrate that PtNP induced apoptosis via mitochondrial pathways by upregulating Bax and Puma and downregulating Bcl-2 proteins, leading to the release of cytochrome c and activation of caspase-3 and caspase-9. As a dual-DNA-damage agent, PtNP is able to improve the anticancer activity by damaging both nuclear and mitochondrial DNA, thus providing a new anticancer mechanism of action for the naphthalimide monofunctional platinum­(II) complexes.
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Mechanistic studies demonstrate that PtNP induced apoptosis via mitochondrial pathways by upregulating Bax and Puma and downregulating Bcl-2 proteins, leading to the release of cytochrome c and activation of caspase-3 and caspase-9. 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Chem</addtitle><date>2019-10-07</date><risdate>2019</risdate><volume>58</volume><issue>19</issue><spage>13150</spage><epage>13160</epage><pages>13150-13160</pages><issn>0020-1669</issn><eissn>1520-510X</eissn><abstract>Mitochondrial DNA (mtDNA) is an attractive cellular target for anticancer agents in addition to nuclear DNA (nDNA). The cationic platinum­(II) complex cis-[Pt­(NP)­(NH3)2Cl]­NO3 (PtNP, NP = N-(2-ethylpyridine)-1,8-naphthalimide) bearing the DNA-intercalating moiety NP was designed. The structure of PtNP was fully characterized by single-crystal X-ray crystallography, NMR, and HRMS. PtNP is superior to cisplatin in both in vitro and in vivo anticancer activities with low systemic toxicity. The interaction of PtNP with CT-DNA demonstrated that PtNP could effectively bind to DNA through both covalent and noncovalent double binding modes. In addition to causing significant damage to nDNA and remarkable inhibition to DNA damage repair, PtNP also distributed in mitochondria, inducing mtDNA damage and affecting the downstream transcriptional level of mitochondrion-encoded genes. In addition, PtNP disturbed the physiological processes of mitochondria by reducing the mitochondrial membrane potential and promoting the generation of reactive oxygen species. Mechanistic studies demonstrate that PtNP induced apoptosis via mitochondrial pathways by upregulating Bax and Puma and downregulating Bcl-2 proteins, leading to the release of cytochrome c and activation of caspase-3 and caspase-9. 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title Enhancing Cytotoxicity of a Monofunctional Platinum Complex via a Dual-DNA-Damage Approach
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