Objective To explore the effects of resveratrol-induced apoptosis and autophagy in T-cell acute lymphoblastic leukemia （T-ALL） cells and potential molecular mechanisms. Methods The anti-proliferation effect of resve...Objective To explore the effects of resveratrol-induced apoptosis and autophagy in T-cell acute lymphoblastic leukemia （T-ALL） cells and potential molecular mechanisms. Methods The anti-proliferation effect of resveratrol-induced, apoptosis and autophagy on T-ALL cells were detected by using MTI- test, immunofluorescence, electronic microscope, and flow cytometry, respectively. Western blotting was performed for detecting changes of apoptosis-associated proteins, cell cycle regulatory proteins and state of activation of Akt, mTOR, p70S6K, 4E-BP1, and p38-MAPK. Results Resveratrol inhibited the proliferation and dose and time-dependent manner. It also induced cyclin-dependent kinase （CDK） inhibitors p21 and induced apoptosis and autophagy in T-ALL cells in a cell cycle arrest at G0/G1 phase via up regulating p27 and down regulating cyclin A and cyclin D1. Western blotting revealed that resveratrol significantly decreased the expression of antiapoptotic proteins （Mcl-1 and Bcl-2） and increased the expression of proapoptotic proteins （Bax, Bim, and Bad）, and induced cleaved-caspase-3 in a time-dependent manner. Significant increase in ratio of LC3-11/LC3-1 and Beclin 1 was also detected. Furthermore, resveratrol induced significant dephosphorylation of Akt, mTOR, p70S6K, and 4E-BP1, but enhanced specific phosphorylation of p38-MAPK which could be blocked by SB203580. When autophagy was suppressed by 3-MA, apoptosis in T-ALL cells induced by resveratrol was enhanced. Conclusion Our findings have suggested that resveratrol induces cell cycle arrest, apoptosis, and autophagy in T-ALL cells through inhibiting Akt/mTOR/p7OS6K/4E-BP1 and activating p38-MAPK signaling pathways. Autophagy might play a role as a self-defense mechanism in T-ALL cells treated by resveratrol. Therefore, the reasonable inhibition of autophagy in T-ALL cells may serve as a promising strategy for resveratrol induced apoptosis and can be used as adjuvant chemotherapy for T-ALL.展开更多
Background Relapse happens frequently after allogeneic hematopoietic cell transplantation （alIo-HCT） in the patients with Philadelphia chromosome-positive acute lymphoblastic leukemia （Ph^＋ ALL）. Detection of the...Background Relapse happens frequently after allogeneic hematopoietic cell transplantation （alIo-HCT） in the patients with Philadelphia chromosome-positive acute lymphoblastic leukemia （Ph^＋ ALL）. Detection of the minimal residual disease （MRD） before and after alIo-HCT is associated with higher relapse rate. Early administration of imatinib after alIo-HCT may prevent recurrent Ph^＋ ALL. The aim of this study was to evaluate the safety and efficacy of imatinib in preventing hematological relapse when imatinib was administrated in the first 90 days after alIo-HCT. Methods Patients with Ph^＋ ALL that underwent alIo-HCT were enrolled in a prospective study. A TaqMan-based real-time quantitative polymerase chain reaction （RQ-PCR） technique was used to detect the MRD （bcr-abl transcript levels）. Imatinib therapy was initiated prior to 90 days after alIo-HCT if the patient＇s absolute neutrophil count （ANC） was above 1.0×10^9/L （without granulocyte colony-stimulating factor （G-CSF） administration） and the platelet count was greater than 50.0×10^9/L, or if the bcr-abl transcript levels were elevated in two consecutive tests, or if the bcr-abl transcript levels were 〉10.2 after the initial engraftment. The initial daily dose of imatinib was 400 mg/d for adults and 260 mg/m^2 for children （younger than 17 years）. Imatinib was administered for at least I month and the bcr-abl TaqMan results were negative for 3 consecutive tests, or complete molecular remission （CR^mol） was sustained for at least 3 months. Results From May 2005 to October 2008, 29 patients were enrolled in this study, of whom, 19 patients were male and 10 were female. The median age of the enrolled patients was 33 years （range 6-50 years）. Imatinib therapy was started at a median time of 60 days （range 20-122 days） post HCT （only one patient started Imatinib therapy at 122nd day after HCT）. Twenty-five adult patients could tolerate a dose of 300-400 mg/d of imatinib, and three children tolerated 展开更多
The cure rate of childhood acute lymphoblastic leukemia(ALL)has exceeded 90%in some contemporary clinical trials.However,the dose intensity of conventional chemotherapy has been pushed to its limit.Further improvement...The cure rate of childhood acute lymphoblastic leukemia(ALL)has exceeded 90%in some contemporary clinical trials.However,the dose intensity of conventional chemotherapy has been pushed to its limit.Further improvement in outcome will need to rely more heavily on molecular therapeutic as well as immuno-and cellular-therapy approaches together with precise risk stratification.Children with ETV6-RUNX1 or hyperdiploid>50 ALL who achieve negative minimal residual disease during early remission induction are suitable candidates for reduction in treatment.Patients with Philadelphia chromosome(Ph)-positive or Ph-like ALL with ABL-class fusion should be treated with dasatinib.BH3 profiling and other preclinical methods have identified several high-risk subtypes,such as hypodiplod,early T-cell precursor,immature T-cell,KMT2A-rearranged,Ph-positive and TCF-HLF-positive ALL,that may respond to BCL-2 inhibitor venetoclax.There are other fusions or mutations that may serve as putative targets,but effective targeted therapy has yet to be established.For other high-risk patients or poor early treatment responders who do not have targetable genetic lesions,current approaches that offer hope include blinatumomab,inotuzumab and CAR-T cell therapy for B-ALL,and daratumumab and nelarabine for T-ALL.With the expanding therapeutic armamentarium,we should start focus on rational combinations of targeted therapy with non-overlapping toxicities.展开更多
目的:观察大剂量甲氨蝶呤(HD-MTX)治疗儿童急性淋巴细胞白血病(ALL)的不良反应及血药浓度。方法:82例ALL患儿作为研究对象,给予HD-MTX治疗,于给药后第42、66 h时采用酶免疫增强法监测MTX血药浓度,并据血药浓度调整甲酰四氢叶酸钙(CF)解...目的:观察大剂量甲氨蝶呤(HD-MTX)治疗儿童急性淋巴细胞白血病(ALL)的不良反应及血药浓度。方法:82例ALL患儿作为研究对象,给予HD-MTX治疗,于给药后第42、66 h时采用酶免疫增强法监测MTX血药浓度,并据血药浓度调整甲酰四氢叶酸钙(CF)解救剂量;观察用药后两个时间点不同MTX血药浓度时患儿的不良反应,不同MTX血药浓度患儿CF解救次数和解救剂量。结果:HD-MTX化疗后,42 h MTX浓度≤1.0μmol/L的ALL患儿CF解救次数、解救剂量及不良反应发生率低于42 h MTX浓度>1.0μmol/L的患儿,差异具有统计学意义(P<0.01);用药后66 h MTX浓度≤3.0μmol/L的ALL患儿CF解救次数、解救剂量及不良反应发生率低于66 h MTX浓度>3.0μmol/L的患儿,差异具有统计学意义(P<0.01)。结论:儿童ALL患者应用HD-MTX治疗,同一时间MTX血药浓度越大不良反应发生率越高,CF解救次数、解救剂量也越高。展开更多
基金supported by grants from the Department of Science and Technology of Sichuan Province,China (No.2008JY0029-1 and No.07FG002-024)research funds from the Program for Changjiang Scholars and Innovative-Research Team in University (No.IRT0935)
文摘Objective To explore the effects of resveratrol-induced apoptosis and autophagy in T-cell acute lymphoblastic leukemia （T-ALL） cells and potential molecular mechanisms. Methods The anti-proliferation effect of resveratrol-induced, apoptosis and autophagy on T-ALL cells were detected by using MTI- test, immunofluorescence, electronic microscope, and flow cytometry, respectively. Western blotting was performed for detecting changes of apoptosis-associated proteins, cell cycle regulatory proteins and state of activation of Akt, mTOR, p70S6K, 4E-BP1, and p38-MAPK. Results Resveratrol inhibited the proliferation and dose and time-dependent manner. It also induced cyclin-dependent kinase （CDK） inhibitors p21 and induced apoptosis and autophagy in T-ALL cells in a cell cycle arrest at G0/G1 phase via up regulating p27 and down regulating cyclin A and cyclin D1. Western blotting revealed that resveratrol significantly decreased the expression of antiapoptotic proteins （Mcl-1 and Bcl-2） and increased the expression of proapoptotic proteins （Bax, Bim, and Bad）, and induced cleaved-caspase-3 in a time-dependent manner. Significant increase in ratio of LC3-11/LC3-1 and Beclin 1 was also detected. Furthermore, resveratrol induced significant dephosphorylation of Akt, mTOR, p70S6K, and 4E-BP1, but enhanced specific phosphorylation of p38-MAPK which could be blocked by SB203580. When autophagy was suppressed by 3-MA, apoptosis in T-ALL cells induced by resveratrol was enhanced. Conclusion Our findings have suggested that resveratrol induces cell cycle arrest, apoptosis, and autophagy in T-ALL cells through inhibiting Akt/mTOR/p7OS6K/4E-BP1 and activating p38-MAPK signaling pathways. Autophagy might play a role as a self-defense mechanism in T-ALL cells treated by resveratrol. Therefore, the reasonable inhibition of autophagy in T-ALL cells may serve as a promising strategy for resveratrol induced apoptosis and can be used as adjuvant chemotherapy for T-ALL.
文摘Background Relapse happens frequently after allogeneic hematopoietic cell transplantation （alIo-HCT） in the patients with Philadelphia chromosome-positive acute lymphoblastic leukemia （Ph^＋ ALL）. Detection of the minimal residual disease （MRD） before and after alIo-HCT is associated with higher relapse rate. Early administration of imatinib after alIo-HCT may prevent recurrent Ph^＋ ALL. The aim of this study was to evaluate the safety and efficacy of imatinib in preventing hematological relapse when imatinib was administrated in the first 90 days after alIo-HCT. Methods Patients with Ph^＋ ALL that underwent alIo-HCT were enrolled in a prospective study. A TaqMan-based real-time quantitative polymerase chain reaction （RQ-PCR） technique was used to detect the MRD （bcr-abl transcript levels）. Imatinib therapy was initiated prior to 90 days after alIo-HCT if the patient＇s absolute neutrophil count （ANC） was above 1.0×10^9/L （without granulocyte colony-stimulating factor （G-CSF） administration） and the platelet count was greater than 50.0×10^9/L, or if the bcr-abl transcript levels were elevated in two consecutive tests, or if the bcr-abl transcript levels were 〉10.2 after the initial engraftment. The initial daily dose of imatinib was 400 mg/d for adults and 260 mg/m^2 for children （younger than 17 years）. Imatinib was administered for at least I month and the bcr-abl TaqMan results were negative for 3 consecutive tests, or complete molecular remission （CR^mol） was sustained for at least 3 months. Results From May 2005 to October 2008, 29 patients were enrolled in this study, of whom, 19 patients were male and 10 were female. The median age of the enrolled patients was 33 years （range 6-50 years）. Imatinib therapy was started at a median time of 60 days （range 20-122 days） post HCT （only one patient started Imatinib therapy at 122nd day after HCT）. Twenty-five adult patients could tolerate a dose of 300-400 mg/d of imatinib, and three children tolerated
基金This work is supported in part by the US National Institute of Health(Nos.P30CA021765,P50GM115279,and R01CA036401)American Lebanese Syrian Associated Charities(ALSAC).
文摘The cure rate of childhood acute lymphoblastic leukemia(ALL)has exceeded 90%in some contemporary clinical trials.However,the dose intensity of conventional chemotherapy has been pushed to its limit.Further improvement in outcome will need to rely more heavily on molecular therapeutic as well as immuno-and cellular-therapy approaches together with precise risk stratification.Children with ETV6-RUNX1 or hyperdiploid>50 ALL who achieve negative minimal residual disease during early remission induction are suitable candidates for reduction in treatment.Patients with Philadelphia chromosome(Ph)-positive or Ph-like ALL with ABL-class fusion should be treated with dasatinib.BH3 profiling and other preclinical methods have identified several high-risk subtypes,such as hypodiplod,early T-cell precursor,immature T-cell,KMT2A-rearranged,Ph-positive and TCF-HLF-positive ALL,that may respond to BCL-2 inhibitor venetoclax.There are other fusions or mutations that may serve as putative targets,but effective targeted therapy has yet to be established.For other high-risk patients or poor early treatment responders who do not have targetable genetic lesions,current approaches that offer hope include blinatumomab,inotuzumab and CAR-T cell therapy for B-ALL,and daratumumab and nelarabine for T-ALL.With the expanding therapeutic armamentarium,we should start focus on rational combinations of targeted therapy with non-overlapping toxicities.
文摘目的:观察大剂量甲氨蝶呤(HD-MTX)治疗儿童急性淋巴细胞白血病(ALL)的不良反应及血药浓度。方法:82例ALL患儿作为研究对象,给予HD-MTX治疗,于给药后第42、66 h时采用酶免疫增强法监测MTX血药浓度,并据血药浓度调整甲酰四氢叶酸钙(CF)解救剂量;观察用药后两个时间点不同MTX血药浓度时患儿的不良反应,不同MTX血药浓度患儿CF解救次数和解救剂量。结果:HD-MTX化疗后,42 h MTX浓度≤1.0μmol/L的ALL患儿CF解救次数、解救剂量及不良反应发生率低于42 h MTX浓度>1.0μmol/L的患儿,差异具有统计学意义(P<0.01);用药后66 h MTX浓度≤3.0μmol/L的ALL患儿CF解救次数、解救剂量及不良反应发生率低于66 h MTX浓度>3.0μmol/L的患儿,差异具有统计学意义(P<0.01)。结论:儿童ALL患者应用HD-MTX治疗,同一时间MTX血药浓度越大不良反应发生率越高,CF解救次数、解救剂量也越高。
