A Dual-Targeting, P53-Independent, Apoptosis-Inducing Platinum( Ii ) Anticancer Complex, [Pt(BDI [superscript QQ] )]Cl
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Author(s)
Suntharalingam, Kogularamanan
Wilson, Justin Jeff
Lin, Wei
Lippard, Stephen J.
Date Issued
January 2014
Journal
Metallomics
Publisher
Royal Society of Chemistry, The
Citation
Suntharalingam, Kogularamanan; Wilson, Justin J.; Lin, Wei and Lippard, Stephen J. “ A Dual-Targeting, P53-Independent, Apoptosis-Inducing Platinum( Ii ) Anticancer Complex, [Pt(BDI [superscript QQ] )]Cl .” Metallomics 6, 3 (January 2014): 437–443 © 2014 The Royal Society of Chemistry
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Author's final manuscript
Abstract
The therapeutic index and cellular mechanism of action of [Pt(BDI[superscript QQ])]Cl, a monocationic, square-planar platinum(II) complex, are reported. [Pt(BDI[superscript 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[superscript 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[superscript QQ])]Cl exhibits dual-threat capabilities, targeting nuclear DNA and mitochondria simultaneously. [Pt(BDI[superscript QQ])]Cl induces DNA damage, leading to p53 enrichment, mitochondrial membrane potential depolarisation, and caspase-mediated apoptosis. [Pt(BDI[superscript QQ])]Cl also accumulates in the mitochondria, resulting in direct mitochondrial damage. Flow cytometric studies demonstrated that [Pt(BDI[superscript QQ])]Cl has no significant effect on cell cycle progression. Remarkably, p53-status is a not a determinant of [Pt(BDI[superscript QQ])]Cl activity. In p53-null cells, [Pt(BDI[superscript QQ])]Cl, induces cell death through mitochondrial dysfunction. Cancers with p53-null status could therefore be targeted using [Pt(BDI[superscript QQ])]Cl.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
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DOI of Published Version
https://doi.org/10.1039/c3mt00364g
