The development of multidrug resistance (MDR) is one of the major challenges to the success of chemotherapy treatment of cancer. This phenomenon is often associated with the overexpression of the ATP-binding cassette ...The development of multidrug resistance (MDR) is one of the major challenges to the success of chemotherapy treatment of cancer. This phenomenon is often associated with the overexpression of the ATP-binding cassette (ABC) transporters P-gp (P-glycoprotein, ABCB1), multidrug resistance-associated protein 1, ABCC1 and breast cancer resistance protein, ABCG2 (BCRP). These transporters are constitutively expressed in many tissues playing relevant protective roles by the regulation of the permeability of biological membranes, but they are also overexpressed in malignant tissues. P-gp is the first efflux transporter discovered to be involved in cancer drug resistance, and over the years, inhibitors of this pump have been disclosed to administer them in combination with chemotherapeutic agents. Three generations of inhibitors of P-gp have been examined in preclinical and clinical studies;however, these trials have largely failed to demonstrate that coadministration of pump inhibitors elicits an improvement in therapeutic efficacy of antitumor agents, although some of the latest compounds show better results. Therefore, new and innovative strategies, such as the fallback to natural products and the discover of dual activity ligands emerged as new perspectives. BCRP is the most recently ABC protein identified to be involved in multidrug resistance. It is overexpressed in several haematological and solid tumours together with P-gp, threatening the therapeutic effectiveness of different chemotherapeutic drugs. The chemistry of recently described BCRP inhibitors and dual P-gp/BCRP inhibitors, as well as their preliminary pharmacological evaluation are discussed, and the most recent advances concerning these kinds of MDR modulators are reviewed.展开更多
An estimated 30,000 men in the United States will die of metastatic prostate cancer(PCa)each year due to the development of therapy resistance,most notably resistance to second-generation antiandrogen enzalutamide.The...An estimated 30,000 men in the United States will die of metastatic prostate cancer(PCa)each year due to the development of therapy resistance,most notably resistance to second-generation antiandrogen enzalutamide.The vast majority of PCa is driven by the androgen receptor(AR).Enzalutamide is an AR antagonist,which extends patient survival and is widely used in the clinic for the treatment of castration-resistant prostate cancer(CRPC);however,many patients will have primary or develop acquired resistance and continue to progress.Characterization of the molecular mechanisms of enzalutamide resistance provides insight into potentially efficacious therapies for enzalutamide-resistant CRPC(ER-CRPC).Understanding these mechanisms is critical for the identification of biomarkers predictive of therapy resistance and the development of therapeutic strategies to target ER-CRPC.展开更多
Resistive random-access memory(RRAM)is a promising technology to develop nonvolatile memory and artificial synaptic devices for brain-inspired neuromorphic computing.Here,we have developed a STO:Ag/SiO_(2) bilayer bas...Resistive random-access memory(RRAM)is a promising technology to develop nonvolatile memory and artificial synaptic devices for brain-inspired neuromorphic computing.Here,we have developed a STO:Ag/SiO_(2) bilayer based memristor that has exhibited a filamentary resistive switching with stable endurance and long-term data retention ability.The memristor also exhibits a tunable resistance modulation under positive and negative pulse trains,which could fully mimic the potentiation and depression behavior like a bio-synapse.Several synaptic plasticity functions,including long-term potentiation(LTP)and long-term depression(LTD),paired-pulsed facilitation(PPF),spike-rate-dependent-plasticity(SRDP),and post-tetanic potentiation(PTP),are faithfully implemented with the fabricated memristor.Moreover,to demonstrate the feasibility of our memristor synapse for neuromorphic applications,spike-timedependent plasticity(STDP)is also investigated.Based on conductive atomic force microscopy observations and electrical transport model analyses,it can be concluded that it is the controlled formation and rupture of Ag filaments that are responsible for the resistive switching while exhibiting a switching ratio of~10;along with a good endurance and stability suitable for nonvolatile memory applications.Before fully electroforming,the gradual conductance modulation of Ag/STO:Ag/SiO_(2)/p^(++)-Si memristor can be realized,and the working mechanism could be explained by the succeeding growth and contraction of Ag filaments promoted by a redox reaction.This newly fabricated memristor may enable the development of nonvolatile memory and realize controllable resistance/weight modulation when applied as an artificial synapse for neuromorphic computing.展开更多
文摘The development of multidrug resistance (MDR) is one of the major challenges to the success of chemotherapy treatment of cancer. This phenomenon is often associated with the overexpression of the ATP-binding cassette (ABC) transporters P-gp (P-glycoprotein, ABCB1), multidrug resistance-associated protein 1, ABCC1 and breast cancer resistance protein, ABCG2 (BCRP). These transporters are constitutively expressed in many tissues playing relevant protective roles by the regulation of the permeability of biological membranes, but they are also overexpressed in malignant tissues. P-gp is the first efflux transporter discovered to be involved in cancer drug resistance, and over the years, inhibitors of this pump have been disclosed to administer them in combination with chemotherapeutic agents. Three generations of inhibitors of P-gp have been examined in preclinical and clinical studies;however, these trials have largely failed to demonstrate that coadministration of pump inhibitors elicits an improvement in therapeutic efficacy of antitumor agents, although some of the latest compounds show better results. Therefore, new and innovative strategies, such as the fallback to natural products and the discover of dual activity ligands emerged as new perspectives. BCRP is the most recently ABC protein identified to be involved in multidrug resistance. It is overexpressed in several haematological and solid tumours together with P-gp, threatening the therapeutic effectiveness of different chemotherapeutic drugs. The chemistry of recently described BCRP inhibitors and dual P-gp/BCRP inhibitors, as well as their preliminary pharmacological evaluation are discussed, and the most recent advances concerning these kinds of MDR modulators are reviewed.
基金This work was supported by the Department of Defense(W81XWH017-1-0674)the Prostate Cancer Foundation(18CHAL16)as well as support from the Cole Foundation and the Wilson Foundation.
文摘An estimated 30,000 men in the United States will die of metastatic prostate cancer(PCa)each year due to the development of therapy resistance,most notably resistance to second-generation antiandrogen enzalutamide.The vast majority of PCa is driven by the androgen receptor(AR).Enzalutamide is an AR antagonist,which extends patient survival and is widely used in the clinic for the treatment of castration-resistant prostate cancer(CRPC);however,many patients will have primary or develop acquired resistance and continue to progress.Characterization of the molecular mechanisms of enzalutamide resistance provides insight into potentially efficacious therapies for enzalutamide-resistant CRPC(ER-CRPC).Understanding these mechanisms is critical for the identification of biomarkers predictive of therapy resistance and the development of therapeutic strategies to target ER-CRPC.
基金financially supported by the National Science Funds for Excellent Young Scholars of China(no.61822106)the Natural Science Foundation of China(no.U19A2070)。
文摘Resistive random-access memory(RRAM)is a promising technology to develop nonvolatile memory and artificial synaptic devices for brain-inspired neuromorphic computing.Here,we have developed a STO:Ag/SiO_(2) bilayer based memristor that has exhibited a filamentary resistive switching with stable endurance and long-term data retention ability.The memristor also exhibits a tunable resistance modulation under positive and negative pulse trains,which could fully mimic the potentiation and depression behavior like a bio-synapse.Several synaptic plasticity functions,including long-term potentiation(LTP)and long-term depression(LTD),paired-pulsed facilitation(PPF),spike-rate-dependent-plasticity(SRDP),and post-tetanic potentiation(PTP),are faithfully implemented with the fabricated memristor.Moreover,to demonstrate the feasibility of our memristor synapse for neuromorphic applications,spike-timedependent plasticity(STDP)is also investigated.Based on conductive atomic force microscopy observations and electrical transport model analyses,it can be concluded that it is the controlled formation and rupture of Ag filaments that are responsible for the resistive switching while exhibiting a switching ratio of~10;along with a good endurance and stability suitable for nonvolatile memory applications.Before fully electroforming,the gradual conductance modulation of Ag/STO:Ag/SiO_(2)/p^(++)-Si memristor can be realized,and the working mechanism could be explained by the succeeding growth and contraction of Ag filaments promoted by a redox reaction.This newly fabricated memristor may enable the development of nonvolatile memory and realize controllable resistance/weight modulation when applied as an artificial synapse for neuromorphic computing.