Intensive cancer treatment with drug combination is widely exploited in the clinic but suffers from inconsistent pharmacokinetics among different therapeutic agents.To overcome it,the emerging nanomedicine offers an u...Intensive cancer treatment with drug combination is widely exploited in the clinic but suffers from inconsistent pharmacokinetics among different therapeutic agents.To overcome it,the emerging nanomedicine offers an unparalleled opportunity for encapsulating multiple drugs in a nano-carrier.Herein,a two-step super-assembled strategy was performed to unify the pharmacokinetics of a peptide and a small molecular compound.In this proof-of-concept study,the bioinformatics analysis firstly revealed the potential synergies towards hepatoma therapy for the associative inhibition of exportin 1(XPO1)and ataxia telangiectasia mutated-Rad3-related(ATR),and then a super-assembled nano-pill(gold nano drug carrier loaded AZD6738 and 97110 amino acids of apoptin(AP)(AA@G))was constructed through camouflaging AZD6738(ATR small-molecule inhibitor)-binding human serum albumin onto the AP-Au supramolecular nanoparticle.As expected,both in vitro and in vivo experiment results verified that the AA@G possessed extraordinary biocompatibility and enhanced therapeutic effect through inducing cell cycle arrest,promoting DNA damage and inhibiting DNA repair of hepatoma cell.This work not only provides a co-delivery strategy for intensive liver cancer treatment with the clinical translational potential,but develops a common approach to unify the pharmacokinetics of peptide and small-molecular compounds,thereby extending the scope of drugs for developing the advanced combination therapy.展开更多
弥漫性大B细胞淋巴瘤(Diffuse large B-cell lymphoma,DLBCL)是一种常见的非霍奇金淋巴瘤,目前患者使用R-CHOP一线治疗方案的5年总生存率在60%~70%。DLBCL的异质性和侵袭性可能会导致一些患者在接受治疗后出现复发或进展为难治性疾病。...弥漫性大B细胞淋巴瘤(Diffuse large B-cell lymphoma,DLBCL)是一种常见的非霍奇金淋巴瘤,目前患者使用R-CHOP一线治疗方案的5年总生存率在60%~70%。DLBCL的异质性和侵袭性可能会导致一些患者在接受治疗后出现复发或进展为难治性疾病。作为核输出受体蛋白,核输出蛋白1(Exportin 1,XPO1)能够将超过220种蛋白及RNA从细胞核转运到细胞质,并优先转运癌蛋白及编码癌蛋白的mRNAs,可能参与肿瘤的发生发展。相关研究表明,XPO1在白血病和淋巴瘤等许多恶性肿瘤中过表达,并在DLBCL等B细胞恶性肿瘤中发生突变。XPO1抑制剂能够靶向抑制XPO1,阻断癌蛋白的核输出;也能限制XPO1与其靶蛋白如肿瘤抑制蛋白(Tumor suppressor protein,TSP)的结合,降低TSP的核输出,在恶性肿瘤中发挥抗癌活性。本文就XPO1抑制剂在DLBCL中的研究进展进行综述。展开更多
Cellular homeostasis crucially relies on the correct nucleocytoplasmic distribution of a vast number of proteins and RNA molecules,which are shuttled in and out of the nucleus by specialized transport receptors.The nu...Cellular homeostasis crucially relies on the correct nucleocytoplasmic distribution of a vast number of proteins and RNA molecules,which are shuttled in and out of the nucleus by specialized transport receptors.The nuclear export receptor XPO1,also called CRM1,mediates the translocation of hundreds of proteins and several classes of RNA to the cytoplasm,and thus regulates critical signaling pathways and cellular functions.The normal function of XPO1 appears to be often disrupted in malignant cells due to gene mutations or,most commonly,aberrant overexpression.Due to its important physiological roles and its frequent alteration in human tumors,XPO1 is a promising target for cancer therapy.XPO1 inhibitors have undergone extensive testing as therapeutic agents in preclinical models of cancer,with promising results.One of these inhibitors,Selinexor,is currently being evaluated in multiple clinical trials of different types of solid tumors and hematological malignancies.Here,we review several key aspects of XPO1 function,as well as the mechanisms that may lead to its alteration in cancer,and provide an update on the status of XPO1 inhibitors being developed as drugs for cancer therapy,including the definitive results of the first clinical trials with Selinexor that have been recently published.展开更多
急性髓性白血病(acute myeloid leukemia,AML)是一种当下常见且难治的血液系统恶性肿瘤,由于其高度异质性和易产生耐药,所以需要不断开发新结构、新机制的治疗药物。核输出蛋白1(exportin 1,XPO1)是核质转运的重要转运受体,其在肿瘤细...急性髓性白血病(acute myeloid leukemia,AML)是一种当下常见且难治的血液系统恶性肿瘤,由于其高度异质性和易产生耐药,所以需要不断开发新结构、新机制的治疗药物。核输出蛋白1(exportin 1,XPO1)是核质转运的重要转运受体,其在肿瘤细胞中高度表达,现已成为抗肿瘤药研发的全新靶标。第一代XPO1抑制剂selinexor近日获美国食品药品管理局(Food and Drug Administration,FDA)批准上市,但存在毒性较大等问题,而由Karyopharm制药公司研发的第二代口服XPO1抑制剂eltanexor,在临床及临床前研究中表现出不易穿透血脑屏障,毒性低和耐受性强等优势,本文就其靶标特点、作用机制、基本信息和临床前试验情况作一概述。展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.:81272488 and 81602802)the Shaanxi Province Innovation Capacity Support Program(Grant No.:2018TD-002).
文摘Intensive cancer treatment with drug combination is widely exploited in the clinic but suffers from inconsistent pharmacokinetics among different therapeutic agents.To overcome it,the emerging nanomedicine offers an unparalleled opportunity for encapsulating multiple drugs in a nano-carrier.Herein,a two-step super-assembled strategy was performed to unify the pharmacokinetics of a peptide and a small molecular compound.In this proof-of-concept study,the bioinformatics analysis firstly revealed the potential synergies towards hepatoma therapy for the associative inhibition of exportin 1(XPO1)and ataxia telangiectasia mutated-Rad3-related(ATR),and then a super-assembled nano-pill(gold nano drug carrier loaded AZD6738 and 97110 amino acids of apoptin(AP)(AA@G))was constructed through camouflaging AZD6738(ATR small-molecule inhibitor)-binding human serum albumin onto the AP-Au supramolecular nanoparticle.As expected,both in vitro and in vivo experiment results verified that the AA@G possessed extraordinary biocompatibility and enhanced therapeutic effect through inducing cell cycle arrest,promoting DNA damage and inhibiting DNA repair of hepatoma cell.This work not only provides a co-delivery strategy for intensive liver cancer treatment with the clinical translational potential,but develops a common approach to unify the pharmacokinetics of peptide and small-molecular compounds,thereby extending the scope of drugs for developing the advanced combination therapy.
基金We thank our colleagues at the UPV/EHU Dr.Sonia Bañuelos(Dept.of Biochemistry and Molecular Biology),Dr.Gorka Prieto(Dept.of Communication Engineering)and Dr.Asier Fullaondo(Dept.of Genetics,Physical Anthropology and Animal Physiology)for their help in preparing Figures 2 and 3.Supported by grants from the Spanish Government MINECO-FEDER(SAF2014-57743-R)the Basque Country Government(IT634-13)the University of the Basque Country(UFI11/20),as well as a fellowship from the Basque Country Government(to MS)。
文摘Cellular homeostasis crucially relies on the correct nucleocytoplasmic distribution of a vast number of proteins and RNA molecules,which are shuttled in and out of the nucleus by specialized transport receptors.The nuclear export receptor XPO1,also called CRM1,mediates the translocation of hundreds of proteins and several classes of RNA to the cytoplasm,and thus regulates critical signaling pathways and cellular functions.The normal function of XPO1 appears to be often disrupted in malignant cells due to gene mutations or,most commonly,aberrant overexpression.Due to its important physiological roles and its frequent alteration in human tumors,XPO1 is a promising target for cancer therapy.XPO1 inhibitors have undergone extensive testing as therapeutic agents in preclinical models of cancer,with promising results.One of these inhibitors,Selinexor,is currently being evaluated in multiple clinical trials of different types of solid tumors and hematological malignancies.Here,we review several key aspects of XPO1 function,as well as the mechanisms that may lead to its alteration in cancer,and provide an update on the status of XPO1 inhibitors being developed as drugs for cancer therapy,including the definitive results of the first clinical trials with Selinexor that have been recently published.
文摘急性髓性白血病(acute myeloid leukemia,AML)是一种当下常见且难治的血液系统恶性肿瘤,由于其高度异质性和易产生耐药,所以需要不断开发新结构、新机制的治疗药物。核输出蛋白1(exportin 1,XPO1)是核质转运的重要转运受体,其在肿瘤细胞中高度表达,现已成为抗肿瘤药研发的全新靶标。第一代XPO1抑制剂selinexor近日获美国食品药品管理局(Food and Drug Administration,FDA)批准上市,但存在毒性较大等问题,而由Karyopharm制药公司研发的第二代口服XPO1抑制剂eltanexor,在临床及临床前研究中表现出不易穿透血脑屏障,毒性低和耐受性强等优势,本文就其靶标特点、作用机制、基本信息和临床前试验情况作一概述。
