Drastic surges in intracellular reactive oxygen species(ROS)induce cell apoptosis,while most chemotherapy drugs lead to the accumulation of ROS.Here,we constructed an organic compound,arsenical N-(4-(1,3,2-dithiarsina...Drastic surges in intracellular reactive oxygen species(ROS)induce cell apoptosis,while most chemotherapy drugs lead to the accumulation of ROS.Here,we constructed an organic compound,arsenical N-(4-(1,3,2-dithiarsinan-2-yl)phenyl)acrylamide(AAZ2),which could prompt the ROS to trigger mitochondrial-dependent apoptosis in gastric cancer(GC).Mechanistically,by targeting pyruvate dehydrogenase kinase 1(PDK1),AAZ2 caused metabolism alteration and the imbalance of redox homeostasis,followed by the inhibition of phosphoinositide-3-kinase(PI3K)/protein kinase B(AKT)/mammalian target of rapamycin(mTOR)pathway and leading to the activation of B-cell lymphoma 2(Bcl2)/Bcl2-associated X(Bax)/caspase-9(Cas9)/Cas3 cascades.Importantly,our in vivo data demonstrated that AAZ2 could inhibit the growth of GC xenograft.Overall,our data suggested that AAZ2 could contribute to metabolic abnormalities,leading to mitochondrial-dependent apoptosis by targeting PDK1 in GC.展开更多
The substitution of an acetate pendant arm on the endocyclic or exocyclic nitrogen atoms of AAZTA with a hydroxybenzyl group results in two regioisomeric Gd(III)complexes with different hydration numbers,thermodynamic...The substitution of an acetate pendant arm on the endocyclic or exocyclic nitrogen atoms of AAZTA with a hydroxybenzyl group results in two regioisomeric Gd(III)complexes with different hydration numbers,thermodynamic stabilities differing by 5.5 log K units and remarkably different kinetic inertness.The ligand functionalized with the phenol group on the exocyclic N atom(AAZ3A-exoHB)forms a Gd(III)complex with remarkably high stability(log K_(GdL)=25.06)thanks to the tight coordination of the phenol group,which presents a rather low protonation constant(log K_(GdHL)=3.22).展开更多
基金supported by the Wuhan University Zhongnan Hospital Translational Medicine and Interdisciplinary Research Joint Fund(No.ZNJC201910),China.
文摘Drastic surges in intracellular reactive oxygen species(ROS)induce cell apoptosis,while most chemotherapy drugs lead to the accumulation of ROS.Here,we constructed an organic compound,arsenical N-(4-(1,3,2-dithiarsinan-2-yl)phenyl)acrylamide(AAZ2),which could prompt the ROS to trigger mitochondrial-dependent apoptosis in gastric cancer(GC).Mechanistically,by targeting pyruvate dehydrogenase kinase 1(PDK1),AAZ2 caused metabolism alteration and the imbalance of redox homeostasis,followed by the inhibition of phosphoinositide-3-kinase(PI3K)/protein kinase B(AKT)/mammalian target of rapamycin(mTOR)pathway and leading to the activation of B-cell lymphoma 2(Bcl2)/Bcl2-associated X(Bax)/caspase-9(Cas9)/Cas3 cascades.Importantly,our in vivo data demonstrated that AAZ2 could inhibit the growth of GC xenograft.Overall,our data suggested that AAZ2 could contribute to metabolic abnormalities,leading to mitochondrial-dependent apoptosis by targeting PDK1 in GC.
文摘The substitution of an acetate pendant arm on the endocyclic or exocyclic nitrogen atoms of AAZTA with a hydroxybenzyl group results in two regioisomeric Gd(III)complexes with different hydration numbers,thermodynamic stabilities differing by 5.5 log K units and remarkably different kinetic inertness.The ligand functionalized with the phenol group on the exocyclic N atom(AAZ3A-exoHB)forms a Gd(III)complex with remarkably high stability(log K_(GdL)=25.06)thanks to the tight coordination of the phenol group,which presents a rather low protonation constant(log K_(GdHL)=3.22).
