Rapamycin interacts synergistically with idarubicin to induce T-leukemia cell apoptosisin vitroand in a mesenchymal stem cell simulated drug-resistant microenvironment via Akt/mammalian target of rapamycin and extracellular signal-related kinase signaling pathways
Kangni WuYanmin ZhaoYing HeBinsheng WangKaili DuShan FuKaimin HuLifei ZhangLizhen LiuYongxian HuYing-Jia WangHe Huang
16
Citation
37
Reference
10
Related Paper
Citation Trend
Abstract:
T-cell acute lymphoblastic leukemias (T-ALLs) are clonal lymphoid malignancies with a poor prognosis, and still a lack of effective treatment. Here we examined the interactions between the mammalian target of rapamycin (mTOR) inhibitor rapamycin and idarubicin (IDA) in a series of human T-ALL cell lines Molt-4, Jurkat, CCRF-CEM and CEM/C1. Co-exposure of cells to rapamycin and IDA synergistically induced T-ALL cell growth inhibition and apoptosis mediated by caspase activation via the intrinsic mitochondrial pathway and extrinsic pathway. Combined treatment with rapamycin and IDA down-regulated Bcl-2 and Mcl-1, and inhibited the activation of phosphoinositide 3-kinase (PI3K)/mTOR and extracellular signal-related kinase (ERK). They also played synergistic pro-apoptotic roles in the drug-resistant microenvironment simulated by mesenchymal stem cells (MSCs) as a feeder layer. In addition, MSCs protected T-ALL cells from IDA cytotoxicity by up-regulating ERK phosphorylation, while rapamycin efficiently reversed this protective effect. Taken together, we confirm the synergistic antitumor effects of rapamycin and IDA, and provide an insight into the potential future clinical applications of combined rapamycin-IDA regimens for treating T-cell malignancies.Keywords:
Idarubicin
Jurkat cells
Sirolimus
Idarubicin
Daunorubicin
Cite
Citations (0)
Twenty-six patients affected by acute leukemia were treated with 4-demethoxydaunorubicin (idarubicin), a new anthracycline compound which in experimental leukemias showed an antitumoral activity superior to daunorubicin (DNR) and doxorubicin (DX), with a higher ratio of active to cardiotoxic doses. A group of 16 patients in relapse received idarubicin at a dosage of 5-6 mg/m2/day for 3 consecutive days; a second group of 6 relapsing and 4 previously untreated cases was treated with a sequential combination of idarubicin and arabinosyl cytosine. In all patients, a significant fall of bone marrow and peripheral blast cells was obtained. These preliminary results suggest that idarubicin has a therapeutic activity against human acute leukemias usually responsive to DNR or DX. The duration of myelosuppression varied from 7 to 50 days, leading in some cases to a high risk of infections. As regards other toxic effects (gastrointestinal, hepatic and acute cardiac toxicity, alopecia), idarubicin appears to be, in our experience, a well-tolerated drug; however, it is too early to comment on delayed cardiac effects.
Idarubicin
Daunorubicin
Concomitant
Therapeutic effect
Cardiotoxicity
Bone marrow suppression
Therapeutic index
Cite
Citations (19)
A collaborative overview, using individual patient data, has been performed to compare idarubicin versus daunorubicin or other anthracyclines, when used with cytosine arabinoside as induction chemotherapy for newly diagnosed acute myeloid leukaemia. There were 1052 patients in five trials versus daunorubicin, 100 in one trial versus doxorubicin, and 745 in one trial versus zorubicin. In the trials of idarubicin versus daunorubicin, early induction failures were similar with the two treatments (20% idarubicin v 18% daunorubicin; P = 0.4), but after day 40 the later induction failures were fewer with idarubicin (17% v 29%; P < 0.0001). Therefore complete remission rates were higher with idarubicin (62% v 53%; P = 0.002). Among remitters, fewer of the patients allocated to idarubicin relapsed ( P = 0.008) but slightly more died in remission, leading to a non‐significant benefit ( P = 0.07) in disease‐free survival. Overall survival in these five trials was significantly better with idarubicin than with daunorubicin (13% v 9% alive at 5 years; P = 0.03). There was a trend ( P = 0.006 for remission rate) for the benefit of idarubicin over daunorubicin to decrease with increasing age. There were no significant differences in outcome in the small trial comparing idarubicin versus doxorubicin, or in the large trial comparing idarubicin versus zorubicin. The induction regimens based on idarubicin achieved, in the particular circumstances of the trials reviewed here, better remission rates and better overall survival than those based on daunorubicin.
Idarubicin
Daunorubicin
Induction chemotherapy
Cite
Citations (162)
Cite
Citations (99)
Experiments from flight- and ground-based model systems suggest that unexpected alterations of the human lymphoblastoid cell line Jurkat, as well as effects on cell growth, metabolism, and apoptosis, can occur in altered gravity conditions. Using a desktop random positioning machine (RPM), we investigated the effects of simulated microgravity on Jurkat cells and their multidrug-resistant subline, Jurkat/A4 cells. The viability of Jurkat/A4 cells decreased after simulated microgravity in contrast with the Jurkat cells. At the same time, the viability between the experimental Jurkat cells and control Jurkat cells was not significantly different. Of note, Jurkat cells appeared as less susceptible to apoptosis than their multidrug-resistant clone Jurkat/A4 cells, whereas cell-cycle analysis showed that the percentage of Jurkat/A4 cells in the S-phase was increased after 72 and 96 h of RPM-simulated microgravity relative to their static counterparts. The differences in Jurkat cells at all phases between static and simulated microgravity were not significant. The surface expression of the intercellular adhesion molecule 3 (ICAM-3)—also known as cluster of differentiation (CD)50—protein was changed for Jurkat/A4 cells following exposure to the RPM. Changes in cell morphology were observed in the Jurkat/A4 cells after 96 h of RPM-simulated microgravity. Thus, we concluded that Jurkat/A4 cells are more sensitive to RPM-simulated microgravity as compared with the parental Jurkat cell line. We also suggest that intercellular adhesion molecule 3 may be an important adhesion molecule involved in the induction of leukocyte apoptosis. The Jurkat/A4 cells with an acquired multidrug resistance phenotype could be a useful model for studying the effects of simulated microgravity and testing anticancer drugs.
Jurkat cells
Cite
Citations (16)
OBJECTIVE: To study the role of MEKK2 on the production of IL-2 in Jurkat cells stimulated by PHA/anti-CD28 antibody. METHODS: The MEKK2 and JNK kinase activities were measured in both dominant negative MEKK2 Jurkat (dnMEKK2 Jurkat) cells and parental Jurkat cells. The AP(1) and IL-2 promotor activities were measured by luciferase activity assay. The IL-2 mRNA and protein were detected by RT-PCR and Western blot. RESULTS: After stimulation by PHA/anti-CD28, JNK was activated in parental Jurkat cells but not in dnMEKK2 Jurkat cells. The luciferase report gene activities of AP1 and IL-2 promotors were increased by 4- and 5-folds in parental cells whereas only by 1 fold in dnMEKK2 Jurkat cells. The level of IL-2 mRNA and IL-2 protein were increased in parental Jurkat cells but not in dnMEKK2 Jurkat cells. CONCLUSION: MEKK2 plays an important role on the production of IL-2 in Jurkat cell stimulated with PHA/anti-CD28 antibody. It is a potential drug target for the treatment of GVHD and autoimmune disease.
Jurkat cells
Cite
Citations (1)
The present study aimed to compare treatment outcome of idarubicin versus doxorubicin in combination with Ara-C as induction therapy for untreated AML patients.This retrospective study included 143 patients with de novo AML. All patients received full dose of standard induction therapy (3 + 7) using anthracyclines (doxorubicin or idarubicin) and cytarabine.The studied groups had comparable CR. No significant differences were noted between the studied groups regarding DFS and OS. The DXR group had significantly lower cost in comparison to IDA group.Idarubicin doesn't have a clear advantage over doxorubicin in treatment of AML.
Idarubicin
Induction chemotherapy
Cite
Citations (8)
Relapse is the major cause of treatment failure in acute lymphoblastic leukemia (ALL), yet there is no established treatment for relapsed ALL.To improve the induction remission rate, we modified the dose of idarubicin in the original Children's Cancer Group (CCG)-1884 protocol, and retrospectively compared the results.Twenty-eight patients diagnosed with relapsed ALL received induction chemotherapy according to the CCG-1884 protocol.Complete remission (CR) rate in all patients after induction chemotherapy was 57%.The idarubicin 10 mg/m 2 /week group showed CR rate of 74%, compared with the 22% CR rate of the idarubicin 12.5 mg/m 2 /week group (p=0.010).Remission failure due to treatment-related mortality (TRM) was 44% and 5.2% in the idarubicin 12.5 mg/m 2 /week and 10 mg/m 2 /week groups, respectively (p=0.011).Overall survival (OS) and 4-yr event-free survival (EFS) were 12.8% and 10.3%, respectively.OS and 4-yr EFS were higher in the idarubicin 10 mg/m 2 /week group (19.3% and 15.6%) than in the 12.5 mg/m 2 /week group (0% and 0%).In conclusion, a modified dose of idarubicin from 12.5 mg/m 2 /week to 10 mg/m 2 /week resulted in an improved CR rate in the treatment of relapsed ALL, which was due to lower TRM.However, despite improved CR rate with modified dose of idarubicin, survival rates were unsatisfactory.
Idarubicin
Induction chemotherapy
Cite
Citations (6)
Objective:To investigate the expression regulation of PD-L1(Programed Death Ligand-1) in Jurkat cell and correlation between the expression of PD-L1(Programed Death Ligand-1,B7-H1) and the activity and apoptosis of Jurkat cell.Methods:IFN-γ and the siRNA(small interfering RNA) targeting to PD-L1 were used to control the expression of PD-L1 in the Jurkat cell.RT-PCR,PCR were used to measure the expression of IL-2 and flow cytometry was used to detected the apoptosis of Jurkat cell.Results:Semi-quantitative β-actin,according template amount to PCR,was used to choose siRNA-A from three different siRNA(siRNA-A,siRNA-B,siRNA-C) which can efficiently and specifically inhibit the expression of PD-L1 in Jurkat Cell.80nM siRNA-A transfect Jurkat Cell,after 24h,the expression of PD-L1 decrease obviously.2000U/ml IFN-γ induced Jurkat Cell,24h later,PD-L1 up-regulated.The expression of PD-L1 in Jurkat Cell negatively correlates with the level of IL-2 secreted by Jurkat Cell by RT-PCR and PCR.And the result from flow cytometry showed increased expression of PD-L1 can reduce the apoptosis of Jurkat Cell.Conclusions:Synthesized siRNA for PD-L1,after transfecting Jurkat cell,could specifically inhibit the expression of PD-L1.IFN-γ in vitro could stimulate Jurkat cell and increase the expression of PD-L1.PD-L1 signal negatively correlates with IL-2 secreted by Jurkat cell,and PD-L1 could inhibit the apoptosis of Jurkat cell.
Jurkat cells
Cite
Citations (0)
To investigate the effect of oridonin on the human acute lymphocytic leukemia cell line Jurkat and its mechanism.Jurkat cells were cultured in vitro and treated with various concentrations (0, 1.25, 2.5, 5, and 10 μmol/L) of oridonin for different lengths of time (24, 48, and 72 hours). The proliferation of Jurkat cells was analyzed by MTT assay. The changes in nuclear morphology were evaluated by fluorescence microscopy at 12 hours after treatment with various concentrations of oridonin. The expression levels of Brg1, P53, and C-myc were determined by semi-quantitative Western blot in Jurkat cells treated with various concentrations of oridonin for 24 hours or 5 μmol/L oridonin for various lengths of time (0, 2, 6, 12, and 24 hours). The expression levels of P53 and C-myc and proliferation of Jurkat cells were evaluated after Brg1 expression was knocked down by Brg1-specific siRNA.Compared with the control group, the proliferation of oridonin-treated Jurkat cells was significantly inhibited in a concentration- and time-dependent manner (P<0.05). According to the florescence microscopic analysis, oridonin treatment led to nuclear pyknosis in Jurkat cells. Compared with the control group, Jurkat cells treated with 5 μmol/L oridonin had reduced expression of Brg1 and C-myc but elevated expression of P53. Brg1 knock-down led to a significant reduction in proliferation of Jurkat cells (P<0.05), up-regulated expression of P53, and down-regulated expression of C-myc.Oridonin can inhibit the proliferation of Jurkat cells, probably via the Brg1 signaling pathway.
Jurkat cells
Cite
Citations (1)