Posted by rob on January 14, 2011 under Uncategorized | 
Amiloride Modulates Alternative Splicing in Leukemic Cells and Resensitizes Bcr-AblT315I Mutant Cells to Imatinib.
Cancer Res. 2011 Jan 11;
Authors: Chang WH, Liu TC, Yang WK, Lee CC, Lin YH, Chen TY, Chang JG
The antihypertensive drug amiloride is being considered as a tactic to improve cancer therapy including that for chronic myelogenous leukemia. In this study, we show that amiloride modulates the alternative splicing of various cancer genes, including Bcl-x, HIPK3, and BCR/ABL, and that this effect is not mainly related to pH alteration, which is a known effect of the drug. Splice modulation involved various splicing factors, with the phosphorylation state of serine-arginine-rich (SR) proteins also altered during the splicing process. Pretreatment with okadaic acid to inhibit protein phosphatase PP1 reversed partially the phosphorylation levels of SR proteins and also the amiloride-modulated yields of Bcl-x(s) and HIPK3 U(-) isoforms. Genome-wide detection of alternative splicing further revealed that many other apoptotic genes were regulated by amiloride, including APAF-1, CRK, and SURVIVIN. Various proteins of the Bcl-2 family and MAPK kinases were found to be involved in amiloride-induced apoptosis. Moreover, the effect of amiloride on mRNA levels of Bcl-x was demonstrated to translate to the protein levels. Cotreatment of K562 and BaF3/Bcr-AblT315I cells with amiloride and imatinib induced more loss of cell viability than either agent alone. Our findings suggest that amiloride may offer a potential treatment option for chronic myelogenous leukemia either alone or in combination with imatinib. Cancer Res; 71(2); 383-92. ©2011 AACR.
PMID: 21224352 [PubMed - as supplied by publisher]
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Posted by rob on under Uncategorized |
[A comparative study of different intervention regimens for chronic myelogenous leukemia post allogeneic hematopoietic stem cell transplantation.]
Zhonghua Xue Ye Xue Za Zhi. 2010 Nov;31(11):758-762
Authors: Xu LP, Liu DH, Liu KY, Chen H, Han W, Zhang XH, Chen YH, Wang Y, Qin YZ, Huang XJ
OBJECTIVE: To study the efficacy and safety of immunotherapy and imatinib mesylate used in early post allogeneic hematopoietic stem cell transplantation (HSCT) for intervention. METHODS: Sixty-four chronic myelogenous leukemia (CML) patients received HSCT were analyzed retrospectively based on bcr-abl kinetics post HSCT. Patients were divided into three groups, imatinib group (n = 13), immunotherapy group (n = 20)and combining both group (n = 31). The primary endpoint is molecular response, the second endpoint is side effect related to intervention. RESULTS: There was no difference among the three groups in converting to bcr-abl negativity (86.0%, 90.0% and 83.9%, respectively, P = 0.126), 4 years cumulative relapse incidence (32.3%, 0% and 16.1%, respectively, P = 0.130) and 4 years OS (90.0%, 89.7%, 83.0%, respectively, P = 0.696). There was a trend of more relapse in Imatinib group than in immunotherapy group (P = 0.052). There were more hematological toxicity in imatinib and combining groups than that in immunotherapy group (30.8%, 38.7%, and 5.0%, respectively, P = 0.001). There was significant difference in the incidence of GVHD among the three groups (P = 0.000), being 95.0%, 0% and 67.7% in immunotherapy, imatinib and combining groups, respectively. Intervention related death occurred in 2 cases, both with discontinuation of CsA, graft failure in another patient with CsA withdrawal. No intervention related death occurred in the other two groups. CONCLUSIONS: All three regimens can give a quick and durable molecular remission in most of the patients, but side effects are different. The choice of regimen should be balanced with toxicity individually. CsA withdrawal is not the best choice for very early intervention, the long-term effect for patients received imatinib alone without GVHD is needed to be studied.
PMID: 21223731 [PubMed - as supplied by publisher]
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[Effect of astragalus polysaccharide on the function and maturation of plasmacytoid dendritic cells from chronic myelogenous leukemia before and after treatment.]
Zhonghua Xue Ye Xue Za Zhi. 2010 Nov;31(11):740-743
Authors: Liu LM, Zhang LS
OBJECTIVE: To explore the effect of astragalus polysaccharide (APS) on the function and maturation of chronic myelogenous leukemia (CML) peripheral blood mononuclear cells (PBMC)-derived plasmacytoid dendritic cells (pDCs). METHODS: CML-derived pDCs were sorted by flow cytometry, and then incubated with APS (at 0, 50, 100 and 200 mg/L). After 24 hours, the concentrations of IFN-?, IL-6, TNF-? were detected with ELISA. Five days later, the cultured cells were collected and analyzed for immotype, morphology and ultramicrostructure. RESULTS: The level of IFN-?, IL-6, TNF-? was significantly higher in samples from CML remission group than that in untreated pDCs, and newly diagnosed pDC (P < 0.05) or untreated group. APS could promote more pDCs differentiating to dendritic cells (DCs) in CML remission group than in untreated-pDCs in a dose-dependant manner (P < 0.05). CONCLUSION: APS can enhance the immune function of pDCs, promote differentiation and maturation of pDCs from CML patients.
PMID: 21223727 [PubMed - as supplied by publisher]
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