Multiple myeloma(MM)is a hematological tumor with high mortality and recurrence rate.Carfilzomib is a new-generation proteasome inhibitor that is used as the first-line therapy for MM.However,the development of drug r...Multiple myeloma(MM)is a hematological tumor with high mortality and recurrence rate.Carfilzomib is a new-generation proteasome inhibitor that is used as the first-line therapy for MM.However,the development of drug resistance is a pervasive obstacle to treating MM.Therefore,elucidating the drug resistance mechanisms is conducive to the formulation of novel therapeutic therapies.To elucidate the mechanisms of carfilzomib resistance,we retrieved the GSE78069 microarray dataset containing carfilzomib-resistant LP-1 MM cells and parental MM cells.Differential gene expression analyses revealed major alterations in the major histocompatibility complex(MHC)and cell adhesion molecules.The upregulation of the tumor necrosis factor(TNF)receptor superfamily member 1A(TNFRSF1A)gene was accompanied by the downregulation of MHC genes and cell adhesion molecules.Furthermore,to investigate the roles of these genes,we established a carfilzomib-resistant cell model and observed that carfilzomib resistance induced TNFRSF1A overexpression and TNFRSF1A silencing reversed carfilzomib resistance and reactivated the expression of cell adhesion molecules.Furthermore,TNFRSF1A silencing suppressed the tumorigenesis of MM cells in immunocompetent mice,indicating that TNFRSF1A may lead to carfilzomib resistance by dampening antitumor immunity.Furthermore,our results indicated that TNFRSF1A overexpression conferred carfilzomib resistance in MM cells and suppressed the expression of MHC genes and cell adhesion molecules.The suppression of MHC genes and cell adhesion molecules may impair the interaction between immune cells and cancer cells to impair antitumor immunity.Future studies are warranted to further investigate the signaling pathway underlying the regulatory role of TNFRSF1A in MM cells.展开更多
Refractory and relapsed multiple myeloma (RRMM) with plasma-cell leukemia (PCL) transformation is highly aggressive and resistant to conventional therapy. Novel therapeutics are needed for RRMM-transformed PCL. Seline...Refractory and relapsed multiple myeloma (RRMM) with plasma-cell leukemia (PCL) transformation is highly aggressive and resistant to conventional therapy. Novel therapeutics are needed for RRMM-transformed PCL. Selinexor [an oral exportin 1 (XPO1) inhibitor], carfilzomib (a second-in-class proteasome inhibitor), pomalidomide (third generation of immunomodulatory drug) are usually used for RRMM, but there are no reports on their application in PCL transformation. We describe a 62-year-old male initially diagnosed with MM IgD-lambda type with complex karyotype and extramedullary plasmacytoma in 2020, and relapsed after five months of autologous stem cell transplantation. Despite the use of various therapies, the patient rapidly developed into PCL over a 4-month period. The patient was started on selinexor, carfilzomib, pomalidomide, and dexamethasone (XKPd) combination as a salvage regimen in July 2021. He achieved fast response in first cycle. Then, he fulfilled third cycle of consolidation treatment and got four-month remission. The success of XKPd therapy in achieving a good response suggests its utility in RRMM transformed-PCL patients, who have exhausted various combinations of drug regimens and have historically poor survival outcomes.展开更多
Carfilzomib has become a new choice for patients with multiple myeloma（MM）.However, the use of carfilzomib single-agent or in combination with other agents in MM patients is not explicitly clarified in clinical prac...Carfilzomib has become a new choice for patients with multiple myeloma（MM）.However, the use of carfilzomib single-agent or in combination with other agents in MM patients is not explicitly clarified in clinical practice. Therefore, we analyzed the effects of carfilzomib and its safety and effectiveness using available clinical trial reports in order to find out the best therapy of carfilzomib. We searched MEDLINE, Embase, Pub Med and Cochrane databases as well as Chinese databases of carfilzomib trials（Jan. 2012 to Sep. 2016） for the MM treatment. Clinical characteristics and outcomes were extracted. Meta-analysis results were expressed as the overall response rate（ORR） and performed by R software. A fixed-effects model or random-effects model was applied based on the heterogeneity among studies. Based on our research standard, we identified 17 prospective studies enrolling 1960 patients.A total of 594 MM patients were enrolled in carfilzomib single-agent clinical trials, and the ORR was 32%（I^2 = 84.9%, P〈0.0001）.A total of 1366 MM patients were enrolled in clinical trials of 10 groups of carfilzomib combination regimens, 1081 patients had a therapeutic effect, and the ORR was79%（I^2 = 91.0%, P〈0.0001）. The most frequent adverse events were fever, nausea, vomiting and other non-hematologic events. Carfilzomib was better tolerated than bortezomib, with a lower incidence of peripheral neuropathy and better therapeutic effects compared with other drugs. In this analysis, the highest ORR was achieved from combination of carfilzomib, lenalidomide and dexamethasone, which had a lower incidence of adverse events and a greater ORR compared with carfilzomib single-agent. Therefore, the combination of carfilzomib, lenalidomide and dexamethasone could be a good therapeutic agent with strong clinical effect. However, this conclusion needs to be validated in future study.展开更多
目的:探讨蛋白酶体抑制剂(PI)相关血栓性微血管病(TMA)的发生规律和临床特点,为临床安全用药提供参考。方法:检索中国知网、万方数据库、维普数据库、PubMed、Web of Science等数据库中收录的PI相关TMA的案例报道,检索时间为建库至2023...目的:探讨蛋白酶体抑制剂(PI)相关血栓性微血管病(TMA)的发生规律和临床特点,为临床安全用药提供参考。方法:检索中国知网、万方数据库、维普数据库、PubMed、Web of Science等数据库中收录的PI相关TMA的案例报道,检索时间为建库至2023年4月30日。对患者基本信息、用药情况、TMA的临床表现、实验室检查、治疗及预后进行汇总分析。结果:纳入文献37篇,涉及患者92例,其中男性46例(占50.00%),女性29例(占31.52%),性别不详17例(占18.48%);平均年龄为(61±13)岁。TMA的中位发病时间为64 d,临床表现以发热、乏力、恶心/呕吐、少尿/无尿为主。因1例患者出现2次TMA,则合计93例次TMA,患者血小板计数明显降低,中位值为19.5×10^(9)/L,其中0~50×10^(9)/L的患者最多(52例次,占55.91%);64例次患者(占68.82%)的血清肌酐水平升高,其中>177~445μmol/L的患者最多(32例次,占34.41%)。停药和支持治疗后(共93例次),76例次患者(占81.72%)痊愈/好转,6例次(占6.45%)有后遗症,5例次(占5.38%)死亡。PI相关TMA中,主要涉及的药物为卡非佐米(67例次,占72.04%)。结论:应重视PI所致TMA,应用PI时应考虑患者性别、药物种类等因素;根据临床表现及实验室检查结果,尽早识别不良反应,保障患者用药安全。展开更多
Proteasome inhibitors have shown remarkable success in the treatment of hematologic neoplasm.There has been a lot of attention to applying these drugs for solid tumor treatment.Recent preclinical study has signified t...Proteasome inhibitors have shown remarkable success in the treatment of hematologic neoplasm.There has been a lot of attention to applying these drugs for solid tumor treatment.Recent preclinical study has signified the effectiveness on cell proliferation inhibition in lung adenocarcinoma treated by carfilzomib(CFZ),a second generation proteasome inhibitor.However,no insight has been gained regarding the mechanism.In this study,we have systematically investigated the CFZ functions in cell proliferation and growth,cell cycle arrest,and apoptosis in lung adenocarcinoma cells.Flow cytometry experiments showed that CFZ significantly induced G2/M cell cycle arrest and apoptosis in lung adenocarcinoma.MTS and colony formation assays revealed that CFZ substantially inhibited survival of lung adenocarcinoma cells.All results were consistently correlated to the upregulation expression of Gadd45a,which is an important gene in modulating cell cycle arrest and apoptosis in response to physiologic and environmental stresses.Here,upregulation of Gadd45a expression was observed after CFZ treatment.Knocking down Gadd45a expression suppressed G2/M arrest and apoptosis in CFZ-treated cells,and reduced cytotoxicity of this drug.The protein expression analysis has further identified that the AKT/FOXO3a pathway is involved in Gadd45a upregulation after CFZ treatment.These findings unveil a novel mechanism of proteasome inhibitor in anti-solid tumor activity,and shed light on novel preferable therapeutic strategy for lung adenocarcinoma.We believe that Gadd45a expression can be a highly promising candidate predictor in evaluating the efficacy of proteasome inhibitors in solid tumor therapy.展开更多
We report herein an efficient catalytic epoxidation reaction for the synthesis of epoxyketone(tert-butyl((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate), which is an important synthetic intermedia...We report herein an efficient catalytic epoxidation reaction for the synthesis of epoxyketone(tert-butyl((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate), which is an important synthetic intermediate of carfilzomib. A series of bioinspired manganese complexes bearing N4 ligands are carefully investigated in the epoxidation of enone precursor with H_2O_2 as oxidant in the presence of carboxylic acid(e.g., acetic acid).展开更多
基金Research Projects-Joint Fund for Applied Basic Research of Kunming Medical University,Yunnan Provincial Department of Science and Technology(No.2018FE001(-113),No.202301AY070001-098)Open project of Yunnan Clinical Medical Center(Nos.2020LCZXKF-XY02,XY06,XY16+1 种基金2022LCZXKF-XY02)Yunnan Health Training Project of High Level Talents(No.D–2018018).
文摘Multiple myeloma(MM)is a hematological tumor with high mortality and recurrence rate.Carfilzomib is a new-generation proteasome inhibitor that is used as the first-line therapy for MM.However,the development of drug resistance is a pervasive obstacle to treating MM.Therefore,elucidating the drug resistance mechanisms is conducive to the formulation of novel therapeutic therapies.To elucidate the mechanisms of carfilzomib resistance,we retrieved the GSE78069 microarray dataset containing carfilzomib-resistant LP-1 MM cells and parental MM cells.Differential gene expression analyses revealed major alterations in the major histocompatibility complex(MHC)and cell adhesion molecules.The upregulation of the tumor necrosis factor(TNF)receptor superfamily member 1A(TNFRSF1A)gene was accompanied by the downregulation of MHC genes and cell adhesion molecules.Furthermore,to investigate the roles of these genes,we established a carfilzomib-resistant cell model and observed that carfilzomib resistance induced TNFRSF1A overexpression and TNFRSF1A silencing reversed carfilzomib resistance and reactivated the expression of cell adhesion molecules.Furthermore,TNFRSF1A silencing suppressed the tumorigenesis of MM cells in immunocompetent mice,indicating that TNFRSF1A may lead to carfilzomib resistance by dampening antitumor immunity.Furthermore,our results indicated that TNFRSF1A overexpression conferred carfilzomib resistance in MM cells and suppressed the expression of MHC genes and cell adhesion molecules.The suppression of MHC genes and cell adhesion molecules may impair the interaction between immune cells and cancer cells to impair antitumor immunity.Future studies are warranted to further investigate the signaling pathway underlying the regulatory role of TNFRSF1A in MM cells.
文摘Refractory and relapsed multiple myeloma (RRMM) with plasma-cell leukemia (PCL) transformation is highly aggressive and resistant to conventional therapy. Novel therapeutics are needed for RRMM-transformed PCL. Selinexor [an oral exportin 1 (XPO1) inhibitor], carfilzomib (a second-in-class proteasome inhibitor), pomalidomide (third generation of immunomodulatory drug) are usually used for RRMM, but there are no reports on their application in PCL transformation. We describe a 62-year-old male initially diagnosed with MM IgD-lambda type with complex karyotype and extramedullary plasmacytoma in 2020, and relapsed after five months of autologous stem cell transplantation. Despite the use of various therapies, the patient rapidly developed into PCL over a 4-month period. The patient was started on selinexor, carfilzomib, pomalidomide, and dexamethasone (XKPd) combination as a salvage regimen in July 2021. He achieved fast response in first cycle. Then, he fulfilled third cycle of consolidation treatment and got four-month remission. The success of XKPd therapy in achieving a good response suggests its utility in RRMM transformed-PCL patients, who have exhausted various combinations of drug regimens and have historically poor survival outcomes.
基金Zhejiang Public Welfare Technology Application Research Project(Grant No.2015C33285)Zhejiang Provincial Natural Science Foundation Project(Grant No.Y14H300005)
文摘Carfilzomib has become a new choice for patients with multiple myeloma（MM）.However, the use of carfilzomib single-agent or in combination with other agents in MM patients is not explicitly clarified in clinical practice. Therefore, we analyzed the effects of carfilzomib and its safety and effectiveness using available clinical trial reports in order to find out the best therapy of carfilzomib. We searched MEDLINE, Embase, Pub Med and Cochrane databases as well as Chinese databases of carfilzomib trials（Jan. 2012 to Sep. 2016） for the MM treatment. Clinical characteristics and outcomes were extracted. Meta-analysis results were expressed as the overall response rate（ORR） and performed by R software. A fixed-effects model or random-effects model was applied based on the heterogeneity among studies. Based on our research standard, we identified 17 prospective studies enrolling 1960 patients.A total of 594 MM patients were enrolled in carfilzomib single-agent clinical trials, and the ORR was 32%（I^2 = 84.9%, P〈0.0001）.A total of 1366 MM patients were enrolled in clinical trials of 10 groups of carfilzomib combination regimens, 1081 patients had a therapeutic effect, and the ORR was79%（I^2 = 91.0%, P〈0.0001）. The most frequent adverse events were fever, nausea, vomiting and other non-hematologic events. Carfilzomib was better tolerated than bortezomib, with a lower incidence of peripheral neuropathy and better therapeutic effects compared with other drugs. In this analysis, the highest ORR was achieved from combination of carfilzomib, lenalidomide and dexamethasone, which had a lower incidence of adverse events and a greater ORR compared with carfilzomib single-agent. Therefore, the combination of carfilzomib, lenalidomide and dexamethasone could be a good therapeutic agent with strong clinical effect. However, this conclusion needs to be validated in future study.
文摘目的:探讨蛋白酶体抑制剂(PI)相关血栓性微血管病(TMA)的发生规律和临床特点,为临床安全用药提供参考。方法:检索中国知网、万方数据库、维普数据库、PubMed、Web of Science等数据库中收录的PI相关TMA的案例报道,检索时间为建库至2023年4月30日。对患者基本信息、用药情况、TMA的临床表现、实验室检查、治疗及预后进行汇总分析。结果:纳入文献37篇,涉及患者92例,其中男性46例(占50.00%),女性29例(占31.52%),性别不详17例(占18.48%);平均年龄为(61±13)岁。TMA的中位发病时间为64 d,临床表现以发热、乏力、恶心/呕吐、少尿/无尿为主。因1例患者出现2次TMA,则合计93例次TMA,患者血小板计数明显降低,中位值为19.5×10^(9)/L,其中0~50×10^(9)/L的患者最多(52例次,占55.91%);64例次患者(占68.82%)的血清肌酐水平升高,其中>177~445μmol/L的患者最多(32例次,占34.41%)。停药和支持治疗后(共93例次),76例次患者(占81.72%)痊愈/好转,6例次(占6.45%)有后遗症,5例次(占5.38%)死亡。PI相关TMA中,主要涉及的药物为卡非佐米(67例次,占72.04%)。结论:应重视PI所致TMA,应用PI时应考虑患者性别、药物种类等因素;根据临床表现及实验室检查结果,尽早识别不良反应,保障患者用药安全。
基金Project supported by the National Natural Science Foundation of China(Nos.81601992,81802986,and 81601029)the Natural Science Foundation of Zhejiang Province(No.LQ16H160008)the Medical and Health Program of Zhejiang Province(No.2019338991),China
文摘Proteasome inhibitors have shown remarkable success in the treatment of hematologic neoplasm.There has been a lot of attention to applying these drugs for solid tumor treatment.Recent preclinical study has signified the effectiveness on cell proliferation inhibition in lung adenocarcinoma treated by carfilzomib(CFZ),a second generation proteasome inhibitor.However,no insight has been gained regarding the mechanism.In this study,we have systematically investigated the CFZ functions in cell proliferation and growth,cell cycle arrest,and apoptosis in lung adenocarcinoma cells.Flow cytometry experiments showed that CFZ significantly induced G2/M cell cycle arrest and apoptosis in lung adenocarcinoma.MTS and colony formation assays revealed that CFZ substantially inhibited survival of lung adenocarcinoma cells.All results were consistently correlated to the upregulation expression of Gadd45a,which is an important gene in modulating cell cycle arrest and apoptosis in response to physiologic and environmental stresses.Here,upregulation of Gadd45a expression was observed after CFZ treatment.Knocking down Gadd45a expression suppressed G2/M arrest and apoptosis in CFZ-treated cells,and reduced cytotoxicity of this drug.The protein expression analysis has further identified that the AKT/FOXO3a pathway is involved in Gadd45a upregulation after CFZ treatment.These findings unveil a novel mechanism of proteasome inhibitor in anti-solid tumor activity,and shed light on novel preferable therapeutic strategy for lung adenocarcinoma.We believe that Gadd45a expression can be a highly promising candidate predictor in evaluating the efficacy of proteasome inhibitors in solid tumor therapy.
基金financial support of this work from the National Natural Science Foundation of China (No. 21473226)Key Research Program of Frontier Sciences, CAS(No. QYZDJ-SSWSLH051)Natural Science Foundation of Jiangsu Province (Nos. BK20161261 and BK20170420)
文摘We report herein an efficient catalytic epoxidation reaction for the synthesis of epoxyketone(tert-butyl((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate), which is an important synthetic intermediate of carfilzomib. A series of bioinspired manganese complexes bearing N4 ligands are carefully investigated in the epoxidation of enone precursor with H_2O_2 as oxidant in the presence of carboxylic acid(e.g., acetic acid).
