title: A dual-targeting, p53-independent, apoptosis-inducing platinum(II) anticancer complex, [Pt(BDI(QQ))]Cl.
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.
authors: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. lippard@mit.edu.
authors: Kogularamanan
authors: K
authors: Suntharalingam
authors: Justin J
authors: JJ
authors: Wilson
authors: Wei
authors: W
authors: Lin
authors: Stephen J
authors: SJ
authors: Lippard
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008024:Ligands; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D009944:Organoplatinum Compounds; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin