Objective:Metabolic disorders are regarded as hallmarks of multiple myeloma(MM)and are responsible for rapid cancer cell proliferation and tumor growth.However,the exact biological roles of metabolites in MM cells hav...Objective:Metabolic disorders are regarded as hallmarks of multiple myeloma(MM)and are responsible for rapid cancer cell proliferation and tumor growth.However,the exact biological roles of metabolites in MM cells have not been fully explored.This study aimed to explore the feasibility and clinical significance of lactate for MM and investigate the molecular mechanism of lactic acid(Lac)in the proliferation of myeloma cells and cell sensitivity to bortezomib(BTZ).Methods:Metabolomic analysis of the serum was carried out to obtain metabolites expression and clinical characteristics in MM patients.The CCK8 assay and flow cytometry were used to detect cell proliferation,apoptosis,and cell cycle changes.Western blotting was used to detect the potential mechanism and apoptosis-and cycle-related protein changes.Results:Lactate was highly expressed in both the peripheral blood and bone marrow of MM patients.It was significantly correlated with Durie-Salmon Staging(DS Staging)and the International Staging System(ISS Staging)and the serum and urinary involved/uninvolved free light chain ratios.Patients with relatively high lactate levels had a poor treatment response.Moreover,in vitro experiments showed that Lac could promote the proliferation of tumor cells and decrease the proportion of G0/G1-phase cells,which was accompanied by an increased proportion of S-phase cells.In addition,Lac could decrease tumor sensitivity to BTZ by disrupting the expression of nuclear factor kappa B subunit 2(NFκB2)and Re1B.Conclusion:Metabolic changes are important in MM cell proliferation and treatment response;lactate could be used as a biomarker in MM and as a therapeutic target to overcome cell resistance to BTZ.展开更多
Bortezomib, a proteasome inhibitor, is an established therapy against plasma cell leukemia—a variant of plasma cell dyscrasias. Its most frequent side effects have been listed as peripheral neuropathy, neuropathic pa...Bortezomib, a proteasome inhibitor, is an established therapy against plasma cell leukemia—a variant of plasma cell dyscrasias. Its most frequent side effects have been listed as peripheral neuropathy, neuropathic pain, thrombocytopenia, and gastrointestinal problems. Allergic skin reaction is a rarely documented side effect in patients receiving bortezomib-based chemotherapy. A combination therapy consisting of intravenous bortezomib, oral Revlimid tablets, and oral dexamethasone tablets has been prescribed for the patient after his recent diagnosis of plasma cell leukemia. While receiving his third treatment cycle, he developed an allergic reaction (skin rash) involving the neck, and wrists, and mild bilateral eye swelling. The infusion was stopped immediately and then ciprofloxacin ophthalmic solution and oral diphenhydramine 25 mg were prescribed to the patient with significant improvement in his clinical condition. He was temporarily taken off bortezomib. At a follow-up visit a week later, a significant improvement was noticed in his condition. Rash had reduced on neck and wrists, and eye swelling had reduced as well. As of the time of writing this case report, he has been temporarily taken off bortezomib, but other medications in the treatment regimen were continued as prescribed.展开更多
蛋白酶体抑制剂(proteasom e inh ib itor)通过抑制26S蛋白酶体活性,激活胱冬肽酶(caspase)-3诱导凋亡,抑制核因子(NF)-κB依赖性基因转录,影响细胞内多种信号级联,破坏维持机体正常内稳态的机制导致肿瘤细胞生长延迟或死亡。V e lcade...蛋白酶体抑制剂(proteasom e inh ib itor)通过抑制26S蛋白酶体活性,激活胱冬肽酶(caspase)-3诱导凋亡,抑制核因子(NF)-κB依赖性基因转录,影响细胞内多种信号级联,破坏维持机体正常内稳态的机制导致肿瘤细胞生长延迟或死亡。V e lcade(化学名Bortezom ib,前用名PS-341)是美国FDA批准的第一个已供临床应用的蛋白酶体抑制剂。临床用于治疗初治或复发性、难治性多发性骨髓瘤,其次为造血组织恶性肿瘤及进展性实体瘤等显示具有良好的抗瘤活性,安全性好,不良反应少。其临床应用研究正在迅速扩展中。展开更多
In this study,we administered a modified schedule of weekly intravenous Bortezomib at 1.6 mg/m 2 with dexamethasone(BD) and compared it to the standard 1.3 mg/m 2 twice-weekly BD regimen in Chinese patients with newly...In this study,we administered a modified schedule of weekly intravenous Bortezomib at 1.6 mg/m 2 with dexamethasone(BD) and compared it to the standard 1.3 mg/m 2 twice-weekly BD regimen in Chinese patients with newly diagnosed multiple myeloma(MM).We assessed the difference in efficacy,safety profile and survival between the once-weekly and twice-weekly cohorts(13 vs.24 patients).The over response rate was similar with both arms of the study,being 77% in the once-weekly schedule and 74.9% in the twice-weekly schedule(P=0.690).The median overall survival was not reached in either schedule.Also,the median progression-free survival and duration of response of the once-weekly schedule did not significantly differ from those of the twice-weekly schedule(8 months vs.10 months,P=0.545 and 6 months vs.7 months,P=0.467 respectively).Peripheral sensory neuropathy and grade 3/4 hematologic toxic effects were more frequently reported in the twice-weekly schedule than the once-weekly schedule,but there was no statistically significant difference.This preliminary experience in Chinese patients with newly diagnosed MM indicated that once-weekly infusion of Bortezomib plus dexamethasone may improve safety without affecting outcome.展开更多
Objective:To explore the effect of bortezomib on migration and invasion of cervical carcinoma HeLa cell and specific molecular mechanism.Methods:The effect of bortezomib on the viability of HeLa cell was measured by M...Objective:To explore the effect of bortezomib on migration and invasion of cervical carcinoma HeLa cell and specific molecular mechanism.Methods:The effect of bortezomib on the viability of HeLa cell was measured by MTT assay.The effect of bortezomib on cell migration and invasion was measured by Transwell assay and invasion experiment respectively.The activation of Akt/mTOR signaling pathway and expression level of MMP2,MMP9 were assayed by western blot.Results:MTT assay indicated bortezomib(2.5 μM.5 μM,10 μM)could inhibit HeLa cell viability,and the inhibitory rate was highest at 48 h.Transwell assay and invasion experiment results showed that bortezomib inhibited HeLa cell migration and invasion.Western blotting assays presented bortezomib could suppress the phosphorylation of Akt and mTOR.and down-regulate the expression of MMP2 and MMP9.Conclusions:These results suggested bortezomib could inhibit migration and invasion in cervical carcinoma HeLa cell,which might be related to Akt/mTOR signal pathway.展开更多
BACKGROUND:Extramedullary pancreatic plasmacy- toma treated with bortezomib is rarely reported. METHODS:We admitted a 53-year-old woman with an asymptomatic mass above the left clavicle for over three months,then an a...BACKGROUND:Extramedullary pancreatic plasmacy- toma treated with bortezomib is rarely reported. METHODS:We admitted a 53-year-old woman with an asymptomatic mass above the left clavicle for over three months,then an asymptomatic swelling of the pancreas was found.A biopsy on the mass and a fine needle aspiration of the pancreas were performed.The diagnosis of extramedullary plasmacytoma(EMP)was made.The patient was initially treated with combination chemotherapy consisting of vincristine,doxorubicin and dexamethasone(VAD regimen).She progressed to painless jaundice during the chemotherapy.Then she was treated with bortezomib and hyper-dose dexamethasone.As a result,she had a near complete remission. RESULTS:The data demonstrated that the diagnosis was EMP of the pancreas.The patient responded very well to bortezomib,while failing to respond to the traditional chemotherapy regimen of VAD. CONCLUSION:EMP of the pancreas is rare.This case gives evidence for an excellent response of EMP of the pancreas to bortezomib.展开更多
Objective:Multiple myeloma(MM)remains incurable with high rates of relapse.New therapeutic drugs are therefore urgently needed to improve the prognosis.JaponiconeA(JA),a natural product isolated from Inula japonica Th...Objective:Multiple myeloma(MM)remains incurable with high rates of relapse.New therapeutic drugs are therefore urgently needed to improve the prognosis.JaponiconeA(JA),a natural product isolated from Inula japonica Thunb,has shown good anti-MM potential.A comprehensive study should therefore be conducted to identify both the in vitro and in vivo mechanisms of the anti-MM effects of JA.Methods:CCK8 assays and flow cytometry were used to detect the proliferation,apoptosis,and cell cycle of MM cell lines when treated with JA.In vivo experiments were conducted using subcutaneous xenograft mouse models.We also identified possible targets and the mechanism of JA using RNA-seq and c-Map databases,and identified the specific targets of JA in bortezomib-sensitive and-resistant MM cell lines using CETSA,DARTS,and rescue experiments.Furthermore,JA and bortezomib were used separately or together to characterize their possible synergistic effects.Results:In vitro,JA inhibited proliferation,and induced apoptosis and G2/M phase arrest in MM cell lines,and selectively killed primary CD138+MM cells.In vivo,JA also demonstrated a strong anti-tumor effect with no observable toxicity.In addition,JA showed synergetic effects in combination with bortezomib,and enhanced the anti-tumor effect of bortezomib in bortezomibresistant cells.CETSA and DARTS confirmed direct binding of JA to NF-κB inhibitor kinase beta(IKKβ),and overexpression of IKKβor knockdown of IκBαpartially rescued the apoptosis induced by JA.Conclusions:JA exhibited strong anti-tumor effects in MM.It sensitized myeloma cells to bortezomib and overcame NF-κB-induced drug resistance by inhibiting IKKβ,providing a new treatment strategy for MM patients.展开更多
BACKGROUND Bortezomib is a first-line drug approved for patients with multiple myeloma (MM) and has significantly increased their overall survival. However, bortezomib-induced peripheral neuropathy (PN) remains a sign...BACKGROUND Bortezomib is a first-line drug approved for patients with multiple myeloma (MM) and has significantly increased their overall survival. However, bortezomib-induced peripheral neuropathy (PN) remains a significant side effect that has led to its discontinuation in some patients. Guillain-Barré syndrome (GBS) is recognized as an immune-mediated PN characterized by the involvement of multiple nerve roots and peripheral nerves and albuminocytologic dissociation in cerebrospinal fluid (CSF) tests. Intravenous immunoglobulin (IVIG) and plasmapheresis are effective. CASE SUMMARY A 45-year-old man diagnosed with stage III MM (λ type) was treated with bortezomib and dexamethasone. Fourteen days after the second course, he complained of intense burning sensation in the lower limbs and hands, loss of tactile sensation, and pain in the distal area of both thighs and in the distal part of both wrist joints. Neurological examination revealed absence of knee and ankle reflexes. CSF examination revealed albuminocytologic dissociation. Nerve conduction studies indicated sensory nerve action potential amplitudes, conduction velocity decrease, and F wave latency prolongation. He was diagnosed as MM complicated with GBS. Subsequently, he was treated with high-dose IVIG (400 mg/kg/d for five days). His symptoms fully resolved without relapse at the 6-month follow-up. CONCLUSION Our case highlights the differential diagnosis and management of complications after bortezomib treatment in MM.展开更多
基金supported by grants from the National Natural Science Foundation of China(No.82070208)the Military Clinical Medical Innovation Project of Xinqiao Hospital(No.2021JSLC0003)+2 种基金the National Natural Science Foundation of Chongqing(No.cstc2020jcyjmsxmX0433)the Translational Research Grant of NCRCH(Nos.2020ZKZC02,2021WWB05)the Chongqing Science and Health Joint Medical Research Project(Nos.2021MSXM226,2023QNXM047).
文摘Objective:Metabolic disorders are regarded as hallmarks of multiple myeloma(MM)and are responsible for rapid cancer cell proliferation and tumor growth.However,the exact biological roles of metabolites in MM cells have not been fully explored.This study aimed to explore the feasibility and clinical significance of lactate for MM and investigate the molecular mechanism of lactic acid(Lac)in the proliferation of myeloma cells and cell sensitivity to bortezomib(BTZ).Methods:Metabolomic analysis of the serum was carried out to obtain metabolites expression and clinical characteristics in MM patients.The CCK8 assay and flow cytometry were used to detect cell proliferation,apoptosis,and cell cycle changes.Western blotting was used to detect the potential mechanism and apoptosis-and cycle-related protein changes.Results:Lactate was highly expressed in both the peripheral blood and bone marrow of MM patients.It was significantly correlated with Durie-Salmon Staging(DS Staging)and the International Staging System(ISS Staging)and the serum and urinary involved/uninvolved free light chain ratios.Patients with relatively high lactate levels had a poor treatment response.Moreover,in vitro experiments showed that Lac could promote the proliferation of tumor cells and decrease the proportion of G0/G1-phase cells,which was accompanied by an increased proportion of S-phase cells.In addition,Lac could decrease tumor sensitivity to BTZ by disrupting the expression of nuclear factor kappa B subunit 2(NFκB2)and Re1B.Conclusion:Metabolic changes are important in MM cell proliferation and treatment response;lactate could be used as a biomarker in MM and as a therapeutic target to overcome cell resistance to BTZ.
文摘Bortezomib, a proteasome inhibitor, is an established therapy against plasma cell leukemia—a variant of plasma cell dyscrasias. Its most frequent side effects have been listed as peripheral neuropathy, neuropathic pain, thrombocytopenia, and gastrointestinal problems. Allergic skin reaction is a rarely documented side effect in patients receiving bortezomib-based chemotherapy. A combination therapy consisting of intravenous bortezomib, oral Revlimid tablets, and oral dexamethasone tablets has been prescribed for the patient after his recent diagnosis of plasma cell leukemia. While receiving his third treatment cycle, he developed an allergic reaction (skin rash) involving the neck, and wrists, and mild bilateral eye swelling. The infusion was stopped immediately and then ciprofloxacin ophthalmic solution and oral diphenhydramine 25 mg were prescribed to the patient with significant improvement in his clinical condition. He was temporarily taken off bortezomib. At a follow-up visit a week later, a significant improvement was noticed in his condition. Rash had reduced on neck and wrists, and eye swelling had reduced as well. As of the time of writing this case report, he has been temporarily taken off bortezomib, but other medications in the treatment regimen were continued as prescribed.
文摘蛋白酶体抑制剂(proteasom e inh ib itor)通过抑制26S蛋白酶体活性,激活胱冬肽酶(caspase)-3诱导凋亡,抑制核因子(NF)-κB依赖性基因转录,影响细胞内多种信号级联,破坏维持机体正常内稳态的机制导致肿瘤细胞生长延迟或死亡。V e lcade(化学名Bortezom ib,前用名PS-341)是美国FDA批准的第一个已供临床应用的蛋白酶体抑制剂。临床用于治疗初治或复发性、难治性多发性骨髓瘤,其次为造血组织恶性肿瘤及进展性实体瘤等显示具有良好的抗瘤活性,安全性好,不良反应少。其临床应用研究正在迅速扩展中。
文摘In this study,we administered a modified schedule of weekly intravenous Bortezomib at 1.6 mg/m 2 with dexamethasone(BD) and compared it to the standard 1.3 mg/m 2 twice-weekly BD regimen in Chinese patients with newly diagnosed multiple myeloma(MM).We assessed the difference in efficacy,safety profile and survival between the once-weekly and twice-weekly cohorts(13 vs.24 patients).The over response rate was similar with both arms of the study,being 77% in the once-weekly schedule and 74.9% in the twice-weekly schedule(P=0.690).The median overall survival was not reached in either schedule.Also,the median progression-free survival and duration of response of the once-weekly schedule did not significantly differ from those of the twice-weekly schedule(8 months vs.10 months,P=0.545 and 6 months vs.7 months,P=0.467 respectively).Peripheral sensory neuropathy and grade 3/4 hematologic toxic effects were more frequently reported in the twice-weekly schedule than the once-weekly schedule,but there was no statistically significant difference.This preliminary experience in Chinese patients with newly diagnosed MM indicated that once-weekly infusion of Bortezomib plus dexamethasone may improve safety without affecting outcome.
基金supported by Tangshan City Science And Technology Research And Development Project(14130246a)
文摘Objective:To explore the effect of bortezomib on migration and invasion of cervical carcinoma HeLa cell and specific molecular mechanism.Methods:The effect of bortezomib on the viability of HeLa cell was measured by MTT assay.The effect of bortezomib on cell migration and invasion was measured by Transwell assay and invasion experiment respectively.The activation of Akt/mTOR signaling pathway and expression level of MMP2,MMP9 were assayed by western blot.Results:MTT assay indicated bortezomib(2.5 μM.5 μM,10 μM)could inhibit HeLa cell viability,and the inhibitory rate was highest at 48 h.Transwell assay and invasion experiment results showed that bortezomib inhibited HeLa cell migration and invasion.Western blotting assays presented bortezomib could suppress the phosphorylation of Akt and mTOR.and down-regulate the expression of MMP2 and MMP9.Conclusions:These results suggested bortezomib could inhibit migration and invasion in cervical carcinoma HeLa cell,which might be related to Akt/mTOR signal pathway.
文摘BACKGROUND:Extramedullary pancreatic plasmacy- toma treated with bortezomib is rarely reported. METHODS:We admitted a 53-year-old woman with an asymptomatic mass above the left clavicle for over three months,then an asymptomatic swelling of the pancreas was found.A biopsy on the mass and a fine needle aspiration of the pancreas were performed.The diagnosis of extramedullary plasmacytoma(EMP)was made.The patient was initially treated with combination chemotherapy consisting of vincristine,doxorubicin and dexamethasone(VAD regimen).She progressed to painless jaundice during the chemotherapy.Then she was treated with bortezomib and hyper-dose dexamethasone.As a result,she had a near complete remission. RESULTS:The data demonstrated that the diagnosis was EMP of the pancreas.The patient responded very well to bortezomib,while failing to respond to the traditional chemotherapy regimen of VAD. CONCLUSION:EMP of the pancreas is rare.This case gives evidence for an excellent response of EMP of the pancreas to bortezomib.
基金This work was supported by the National Natural Science Foundation of China(Grant Nos.81970192 and 81670198).
文摘Objective:Multiple myeloma(MM)remains incurable with high rates of relapse.New therapeutic drugs are therefore urgently needed to improve the prognosis.JaponiconeA(JA),a natural product isolated from Inula japonica Thunb,has shown good anti-MM potential.A comprehensive study should therefore be conducted to identify both the in vitro and in vivo mechanisms of the anti-MM effects of JA.Methods:CCK8 assays and flow cytometry were used to detect the proliferation,apoptosis,and cell cycle of MM cell lines when treated with JA.In vivo experiments were conducted using subcutaneous xenograft mouse models.We also identified possible targets and the mechanism of JA using RNA-seq and c-Map databases,and identified the specific targets of JA in bortezomib-sensitive and-resistant MM cell lines using CETSA,DARTS,and rescue experiments.Furthermore,JA and bortezomib were used separately or together to characterize their possible synergistic effects.Results:In vitro,JA inhibited proliferation,and induced apoptosis and G2/M phase arrest in MM cell lines,and selectively killed primary CD138+MM cells.In vivo,JA also demonstrated a strong anti-tumor effect with no observable toxicity.In addition,JA showed synergetic effects in combination with bortezomib,and enhanced the anti-tumor effect of bortezomib in bortezomibresistant cells.CETSA and DARTS confirmed direct binding of JA to NF-κB inhibitor kinase beta(IKKβ),and overexpression of IKKβor knockdown of IκBαpartially rescued the apoptosis induced by JA.Conclusions:JA exhibited strong anti-tumor effects in MM.It sensitized myeloma cells to bortezomib and overcame NF-κB-induced drug resistance by inhibiting IKKβ,providing a new treatment strategy for MM patients.
基金Supported by National Natural Science Foundation of China,No.81660038
文摘BACKGROUND Bortezomib is a first-line drug approved for patients with multiple myeloma (MM) and has significantly increased their overall survival. However, bortezomib-induced peripheral neuropathy (PN) remains a significant side effect that has led to its discontinuation in some patients. Guillain-Barré syndrome (GBS) is recognized as an immune-mediated PN characterized by the involvement of multiple nerve roots and peripheral nerves and albuminocytologic dissociation in cerebrospinal fluid (CSF) tests. Intravenous immunoglobulin (IVIG) and plasmapheresis are effective. CASE SUMMARY A 45-year-old man diagnosed with stage III MM (λ type) was treated with bortezomib and dexamethasone. Fourteen days after the second course, he complained of intense burning sensation in the lower limbs and hands, loss of tactile sensation, and pain in the distal area of both thighs and in the distal part of both wrist joints. Neurological examination revealed absence of knee and ankle reflexes. CSF examination revealed albuminocytologic dissociation. Nerve conduction studies indicated sensory nerve action potential amplitudes, conduction velocity decrease, and F wave latency prolongation. He was diagnosed as MM complicated with GBS. Subsequently, he was treated with high-dose IVIG (400 mg/kg/d for five days). His symptoms fully resolved without relapse at the 6-month follow-up. CONCLUSION Our case highlights the differential diagnosis and management of complications after bortezomib treatment in MM.
