| Literature DB >> 24514456 |
Kogularamanan Suntharalingam1, Justin J Wilson, Wei Lin, Stephen J Lippard.
Abstract
The therapeutic index and cellular mechanism of action of [Pt(BDI(QQ))]Cl, a monocationic, square-planar platinum(II) complex, are reported. [Pt(BDI(QQ))]Cl was used to treat several cell lines, including wild type and cisplatin-resistant ovarian carcinoma cells (A2780 and A2780CP70) and non-proliferating lung carcinoma cells (A549). [Pt(BDI(QQ))]Cl selectively kills cancer cells over healthy cells and exhibits no cross-resistance with cisplatin. The mechanism of cell killing was established through detailed cell-based assays. [Pt(BDI(QQ))]Cl exhibits dual-threat capabilities, targeting nuclear DNA and mitochondria simultaneously. [Pt(BDI(QQ))]Cl induces DNA damage, leading to p53 enrichment, mitochondrial membrane potential depolarisation, and caspase-mediated apoptosis. [Pt(BDI(QQ))]Cl also accumulates in the mitochondria, resulting in direct mitochondrial damage. Flow cytometric studies demonstrated that [Pt(BDI(QQ))]Cl has no significant effect on cell cycle progression. Remarkably, p53-status is a not a determinant of [Pt(BDI(QQ))]Cl activity. In p53-null cells, [Pt(BDI(QQ))]Cl induces cell death through mitochondrial dysfunction. Cancers with p53-null status could therefore be targeted using [Pt(BDI(QQ))]Cl.Entities:
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Year: 2014 PMID： 24514456 PMCID： PMC4082332 DOI： 10.1039/c3mt00364g
Source DB: PubMed Journal: Metallomics ISSN： 1756-5901 Impact factor: 4.526