scholarly journals Inhibition of the NADPH oxidase regulates heme oxygenase 1 expression in chronic myeloid leukemia

Cancer ◽  
2011 ◽  
Vol 118 (13) ◽  
pp. 3433-3445 ◽  
Author(s):  
Melissa M. Singh ◽  
Mary E. Irwin ◽  
Yin Gao ◽  
Kechen Ban ◽  
Ping Shi ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Nadph Oxidase ◽  
Heme Oxygenase ◽  
Myeloid Leukemia ◽  
Heme Oxygenase 1

Targeting of heat shock protein 32 (Hsp32)/heme oxygenase-1 (HO-1) in leukemic cells in chronic myeloid leukemia: a novel approach to overcome resistance against imatinib

Blood ◽  
2008 ◽  
Vol 111 (4) ◽  
pp. 2200-2210 ◽  
Author(s):  
Matthias Mayerhofer ◽  
Karoline V. Gleixner ◽  
Julia Mayerhofer ◽  
Gregor Hoermann ◽  
Eva Jaeger ◽  
...  
Keyword(s):  
Heat Shock ◽  
Chronic Myeloid Leukemia ◽  
Heat Shock Protein ◽  
Heme Oxygenase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Leukemic Cells ◽  
Heme Oxygenase 1 ◽  
Abl Tyrosine Kinase ◽  
Imatinib Resistant

Resistance toward imatinib and other BCR/ABL tyrosine kinase inhibitors remains an increasing clinical problem in the treatment of advanced stages of chronic myeloid leukemia (CML). We recently have identified the heat shock protein 32 (Hsp32)/heme oxygenase-1 (HO-1) as a BCR/ABL-dependent survival molecule in CML cells. We here show that silencing Hsp32/HO-1 in CML cells by an siRNA approach results in induction of apoptosis. Moreover, targeting Hsp32/HO-1 by either pegylated zinc protoporphyrine (PEG-ZnPP) or styrene maleic acid-micelle–encapsulated ZnPP (SMA-ZnPP) resulted in growth inhibition of BCR/ABL-transformed cells. The effects of PEG-ZnPP and SMA-ZnPP were demonstrable in Ba/F3 cells carrying various imatinib-resistant mutants of BCR/ABL, including the T315I mutant, which exhibits resistance against all clinically available BCR/ABL tyrosine kinase inhibitors. Growth-inhibitory effects of PEG-ZnPP and SMA-ZnPP also were observed in the CML-derived human cell lines K562 and KU812 as well as in primary leukemic cells obtained from patients with freshly diagnosed CML or imatinib-resistant CML. Finally, Hsp32/HO-1–targeting compounds were found to synergize with either imatinib or nilotinib in producing growth inhibition in imatinib-resistant K562 cells and in Ba/F3 cells harboring the T315I mutant of BCR/ABL. In summary, these data show that HO-1 is a promising novel target in imatinib-resistant CML.

scholarly journals Over-Expression of Heme Oxygenase-1 in Peripheral Blood Predicts the Progression and Relapse Risk of Chronic Myeloid leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5181-5181
Author(s):  
Jishi Wang ◽  
Sixi Wei ◽  
Yating Wang ◽  
Qixiang Chai ◽  
Qin Fang ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Heme Oxygenase ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Linear Regression Analysis ◽  
Wilcoxon Test ◽  
Expression Level ◽  
Heme Oxygenase 1 ◽  
Cutoff Values ◽  
The Relationship

Abstract Background There are limited eligible clinical markers at present to monitor the progress of chronic myeloid leukemia (CML). Heme oxygenase-1 (HO-1), as one of the most important oxidation-regulating enzymes in vivo, suggests the onset and progression of cancer when highly expressed. Furthermore, HO-1 level is related with the occurrence and development of hematological diseases. But the relationship between HO-1 expression and progression/relapse of CML has seldom been studied hitherto. This study aimed to investigate the relationship between them to find out a new molecular marker for prediction. Methods A total of 60 peripheral blood and bone marrow (BM) samples from 25 CML patients in different phases were collected respectively to detect the expressions of HO-1 and bcr/abl using real-time PCR. Routine blood test was performed to detect the changes of leukocyte and platelet counts. The proportion of primitive cells in BM was detected by flow cytometry. The relationship between high HO-1 expression and CML progression and relapse was explored by the analysis of variance by Wilcoxon test and linear regression analysis. The diagnostic accuracy and cutoff values were determined by receiver operating characteristic curve. Results Relative expression of HO-1 mRNA in CML patients peripheral blood was significantly higher than that of donors (P <0.0001), which were 0.57±3.78 and (1.417±1.125)×10–6, respectively. HO-1 expression level in CML patients was 0.061 5±0.062 4, which decreased to 0.009 4±0.006 7 upon CMoR, and remained remarkably higher 0.016 3±0.017 5 than that of normal donors (1.417±1.125)×10–6, P <0.001. When relapse occurred, HO-1 expression significantly increased from 0.020 6±0.021 0 to 3.852±10.285 in CMoR stage and undergoing relapse. According to progression of CML, HO-1 expression level in CML patients increased from CP (0.009 5±0.017 6) to AP (0.028 0±0.055 7) and then to BP (0.276 7± 0.447 0) . And there was a linear correlation between HO-1 expression and proportion of primitive CML cells. The diagnostic accuracies and cutoff values of HO-1 expression for CML-CP, CML-AP, and CML-BP were 1.0, 0.748, and 0.965, respectively, as well as 0.000 070, 0.001 917, and 0.020 696, respectively. Conclusion HO-1 may be a potential molecular indicator for the progression and relapse of CML. Disclosures No relevant conflicts of interest to declare.

scholarly journals Identification of Heme Oxygenase-1 As a Novel BCR/ABL-Dependent Survival Factor in Chronic Myeloid Leukemia

2004 ◽  
Vol 64 (9) ◽  
pp. 3148-3154 ◽  
Author(s):  
Matthias Mayerhofer ◽  
Stefan Florian ◽  
Maria-Theresa Krauth ◽  
Karl J. Aichberger ◽  
Martin Bilban ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Heme Oxygenase ◽  
Myeloid Leukemia ◽  
Heme Oxygenase 1 ◽  
Survival Factor

Induction of Na+-H+ Ion Exchanger 1 Protein By Heme Oxygenase-1 Plays a Crucial Role in Imatinib-Resistant Chronic Myeloid Leukemia Cells Via p38/MAPK Signaling Pathway

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5513-5513
Author(s):  
Jishi Wang ◽  
Dan Ma
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Real Time ◽  
Signaling Pathway ◽  
P38 Mapk ◽  
Heme Oxygenase ◽  
Myeloid Leukemia ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Heme Oxygenase 1 ◽  
Pkc Β

Abstract Background: Resistance toward imatinib (IM) and other BCR/ABL tyrosine kinase inhibitors(TKI) remains an increasing clinical problem in the treatment of advanced stages of chronic myeloid leukemia (CML). Heme oxygenase-1 (HO-1), as a Bcr/Abl-dependent survival molecule in CML cells, is important to resist against TKI in patients with freshly diagnosed CML or IM-resistant CML. However, the resistant mechanism on HO-1 up-regulation was still unclear. Objective: In this study, our findings indicated that over-expression of Na+-H+ion exchanger 1 protein (NHE1) companied with HO-1 up-regulation in CML patients’ mononuclear cells who resisted with IM, while not in whom was sensitive to IM. Therefore, we explored the difference in the signaling pathway related to HO-1 and NHE1 in IM-resistant or sensitive CML cell lines. Method: CCK-8 kits was used to determine the proliferation inhibition of cells. Flow cytometry was used for analyzing cell proliferation rate and apoptosis. Real-time PCR Array was used to search the relative pathway. Apoptosis relative factors expression were detected by real-time transcription and Western blot. Result: As a result, we found that up-regulation of NHE1 after transfection of K562 cells line with lentivirus vector, lenti-TOPO-EGFP-HO-1. However, this effect disappeared when HO-1 expression was inhibited by transfection with lenti-U6.2-EGFP-siHO-1. Then, the relationship between HO-1 and NHE1 was detected by qPCR array, activation of p38/MAPK pathway mediated by protein kinase C-β II(PKC-β II) was found. NHE1 wasn’t up-regulated as PKC-β was blocked as well as p38/MAPK pathway was inhibited by SB203580 in K562/IM cells. Meanwhile, the apoptotic rate of the IM-resistant cells line K562 was increased by silencing HO-1, or treatment with SB203580, Enzastaurin, and Cariporide alone. Conclusion: In this study, we demonstrated that HO-1 relative IM-resistance in CML was involved in the regulation of NHE-1 phosphorylation, which mediated by p38/MAPK signaling pathway activated by PKC-β. Disclosures No relevant conflicts of interest to declare.

Nuclear Translocation of Heme Oxygenase-1 Confers Resistance to Imatinib in Chronic Myeloid Leukemia Cells

2013 ◽  
Vol 19 (15) ◽  
pp. 2765-2770 ◽  
Author(s):  
Daniele Tibullo ◽  
Ignazio Barbagallo ◽  
Cesarina Giallongo ◽  
Piera La Cava ◽  
Nunziatina Parrinello ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Heme Oxygenase ◽  
Myeloid Leukemia ◽  
Nuclear Translocation ◽  
Leukemia Cells ◽  
Heme Oxygenase 1
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