TY - JOUR
T1 - A dual-targeting, p53-independent, apoptosis-inducing platinum(II) anticancer complex, [Pt(BDIQQ)]Cl
AU - Suntharalingam, Kogularamanan
AU - Wilson, Justin J.
AU - Lin, Wei
AU - Lippard, Stephen J.
PY - 2014/3
Y1 - 2014/3
N2 - The therapeutic index and cellular mechanism of action of [Pt(BDI QQ)]Cl, a monocationic, square-planar platinum(II) complex, are reported. [Pt(BDIQQ)]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(BDIQQ)]Cl exhibits dual-threat capabilities, targeting nuclear DNA and mitochondria simultaneously. [Pt(BDIQQ)]Cl induces DNA damage, leading to p53 enrichment, mitochondrial membrane potential depolarisation, and caspase-mediated apoptosis. [Pt(BDIQQ)]Cl also accumulates in the mitochondria, resulting in direct mitochondrial damage. Flow cytometric studies demonstrated that [Pt(BDIQQ)]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(BDIQQ)]Cl induces cell death through mitochondrial dysfunction. Cancers with p53-null status could therefore be targeted using [Pt(BDIQQ)]Cl.
AB - The therapeutic index and cellular mechanism of action of [Pt(BDI QQ)]Cl, a monocationic, square-planar platinum(II) complex, are reported. [Pt(BDIQQ)]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(BDIQQ)]Cl exhibits dual-threat capabilities, targeting nuclear DNA and mitochondria simultaneously. [Pt(BDIQQ)]Cl induces DNA damage, leading to p53 enrichment, mitochondrial membrane potential depolarisation, and caspase-mediated apoptosis. [Pt(BDIQQ)]Cl also accumulates in the mitochondria, resulting in direct mitochondrial damage. Flow cytometric studies demonstrated that [Pt(BDIQQ)]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(BDIQQ)]Cl induces cell death through mitochondrial dysfunction. Cancers with p53-null status could therefore be targeted using [Pt(BDIQQ)]Cl.
UR - http://www.scopus.com/inward/record.url?scp=84896805713&partnerID=8YFLogxK
U2 - 10.1039/c3mt00364g
DO - 10.1039/c3mt00364g
M3 - Article
C2 - 24514456
AN - SCOPUS:84896805713
SN - 1756-5901
VL - 6
SP - 437
EP - 443
JO - Metallomics
JF - Metallomics
IS - 3
ER -
