Chronic lymphocytic leukaemia （CLL） is a rare blood cancer that always relapses as refractory disease and eventually leads to death. To date, therapeutic options for CLL patients are scarce and there is an urgent ne...Chronic lymphocytic leukaemia （CLL） is a rare blood cancer that always relapses as refractory disease and eventually leads to death. To date, therapeutic options for CLL patients are scarce and there is an urgent need to develop novel chemotherapeutics that are both effective and safe. Gold-containing compounds induce a lethal oxidative and endoplasmic reticulum stress response in cultured and primary CLL cells via inhibition of thioredoxin reductase （TrxR）. However, traditional gold-containing medicines have revealed side effects during clinical applications. Therefore, safer gold-containing drugs are needed to overcome this challenge. In this study, a novel peptide templated gold cluster Au2sSv9 was synthesized and its therapeutic effect on CLL cells was evaluated. This nanocluster could induce cell apoptosis in MEC-1 cells in a dose-dependent manner which correlated with the uptake amount of clusters in cells. As expected, increasing intracellular reactive oxidative species （ROS） in MEC-1 cells was exhibited with the increase of cluster dosage. Further analyses demonstrated the underlying mechanism that the nan- oclusters suppress the activity ofTrxR1, increase the level of intracellular ROS, destroy the mitochondrial membrane potential and finally trigger the mitochondrial apoptotic pathway in MEC-1 cells. Furthermore, the direct interaction between Au2sSv9 clusters and TrxRl was confirmed for the first time by isothermal titration calorimetry. These findings explored the preclinical efficacy and potential mech- anism of gold clusters in CLL therapy and provided a fundamental reference for the development of other novel gold-containing chemotherapeutics to treat CLL.展开更多
基金supported by the National Key Basic Research Program of China (2013CB932703)the National Natural Science Foundation of China (21425522, 81472851, 31670976, 21390410, 31571026, 31500815, 51571185, and 21675157)Beijing Natural Science Foundation (7152158)
文摘Chronic lymphocytic leukaemia （CLL） is a rare blood cancer that always relapses as refractory disease and eventually leads to death. To date, therapeutic options for CLL patients are scarce and there is an urgent need to develop novel chemotherapeutics that are both effective and safe. Gold-containing compounds induce a lethal oxidative and endoplasmic reticulum stress response in cultured and primary CLL cells via inhibition of thioredoxin reductase （TrxR）. However, traditional gold-containing medicines have revealed side effects during clinical applications. Therefore, safer gold-containing drugs are needed to overcome this challenge. In this study, a novel peptide templated gold cluster Au2sSv9 was synthesized and its therapeutic effect on CLL cells was evaluated. This nanocluster could induce cell apoptosis in MEC-1 cells in a dose-dependent manner which correlated with the uptake amount of clusters in cells. As expected, increasing intracellular reactive oxidative species （ROS） in MEC-1 cells was exhibited with the increase of cluster dosage. Further analyses demonstrated the underlying mechanism that the nan- oclusters suppress the activity ofTrxR1, increase the level of intracellular ROS, destroy the mitochondrial membrane potential and finally trigger the mitochondrial apoptotic pathway in MEC-1 cells. Furthermore, the direct interaction between Au2sSv9 clusters and TrxRl was confirmed for the first time by isothermal titration calorimetry. These findings explored the preclinical efficacy and potential mech- anism of gold clusters in CLL therapy and provided a fundamental reference for the development of other novel gold-containing chemotherapeutics to treat CLL.
