Monofunctional Pt(Ⅱ)complexes represent a class of antitumor agents that may expand the antitumor spectrum and overcome the drug resistance of the clinically used cisplatin and its derivatives.Herein,we designed thre...Monofunctional Pt(Ⅱ)complexes represent a class of antitumor agents that may expand the antitumor spectrum and overcome the drug resistance of the clinically used cisplatin and its derivatives.Herein,we designed three novel monofunctional Pt(Ⅱ)complexes,namely,MPL-Ⅰ,MPL-Ⅱand MPL-Ⅲ,by anchoring lonidamine(an inhibitor of mitochondrial hexokinase)to the Pt(Ⅱ)centre for the selective de-energization of cancer cells.Among them,MPL-Ⅲis more potent than cisplatin against triple negative breast cancer MDA-MB-231 cells and exhibits relatively lower cytotoxicity on breast epithelial cells.Intracellular distri bution studies reveal that MPL-Ⅲmainly accumulates in the mitochondria.Furthermore,MPL-Ⅲinduces detrimental changes in the mitochondrial ultrastructure and significant loss of the mitochondrial mem brane potential,inhibits glycolysis and disrupts mitochondrial respiration.As a consequence,MPL-Ⅲcauses cell cycle arrest in the G0/G1 phase,and mitochondria-mediated apoptosis involving caspase acti vation and cytochrome c release.RNA-sequencing data show that MPL-Ⅲperturbs the pathways includ ing DNA damage,metabolic process and transcription regulator activity.Our research provides an in depth study and a new design strategy for effective mono-functional platinum complexes with action mechanisms distinct from those of the clinical platinum-based anticancer drugs.展开更多
基金supported by the National Natural Science Foundation of China(no.21778078,91953117 and 21837006)the innovative team of Ministry of Education(no.IRT_17R111)+1 种基金the Guangdong Natural Science Foundation(2015A030306023)the Fundamental Research Funds for the Central Universities.
文摘Monofunctional Pt(Ⅱ)complexes represent a class of antitumor agents that may expand the antitumor spectrum and overcome the drug resistance of the clinically used cisplatin and its derivatives.Herein,we designed three novel monofunctional Pt(Ⅱ)complexes,namely,MPL-Ⅰ,MPL-Ⅱand MPL-Ⅲ,by anchoring lonidamine(an inhibitor of mitochondrial hexokinase)to the Pt(Ⅱ)centre for the selective de-energization of cancer cells.Among them,MPL-Ⅲis more potent than cisplatin against triple negative breast cancer MDA-MB-231 cells and exhibits relatively lower cytotoxicity on breast epithelial cells.Intracellular distri bution studies reveal that MPL-Ⅲmainly accumulates in the mitochondria.Furthermore,MPL-Ⅲinduces detrimental changes in the mitochondrial ultrastructure and significant loss of the mitochondrial mem brane potential,inhibits glycolysis and disrupts mitochondrial respiration.As a consequence,MPL-Ⅲcauses cell cycle arrest in the G0/G1 phase,and mitochondria-mediated apoptosis involving caspase acti vation and cytochrome c release.RNA-sequencing data show that MPL-Ⅲperturbs the pathways includ ing DNA damage,metabolic process and transcription regulator activity.Our research provides an in depth study and a new design strategy for effective mono-functional platinum complexes with action mechanisms distinct from those of the clinical platinum-based anticancer drugs.
