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

Cancer 2012 Jul 2;118(13):3433-45. Epub 2011 Dec 2.

Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: Patients with chronic myelogenous leukemia (CML) in blast crisis have a poor response to tyrosine kinase inhibitors designed to inhibit the breakpoint cluster region-v-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL1) oncogene. Recent work has demonstrated that heme oxygenase 1 (HO-1) expression is increased in BCR-ABL1-expressing cells and that the inhibition of HO-1 in CML leads to reduced cellular growth, suggesting that HO-1 may be a plausible target for therapy. The objective of the current study was to clarify the mechanism of HO-1 overexpression and the role of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase as a contributor to this mechanism in CML.

Methods: HO-1 expression was evaluated in bone marrow specimens from patients with CML in various stages of disease, in a transplantation-based model for CML, and in CML cell lines. Chemical and genetic inhibition of the NADPH oxidase was carried out in CML cells.

Results: Specimens from patients with CML in blast crisis displayed higher levels of HO-1 staining than specimens from patients with CML in chronic or accelerated phase. HO-1 up-regulation in BCR-ABL1-expressing cells was suppressed by diphenyleneiodonium (DPI), a chemical inhibitor of the NADPH oxidase. Targeting the NADPH oxidase through RNA interference (RNAi) to Ras-related C3 botulinum toxin substrate 1 (Rac1), a dominant-negative Rac1 construct or an inhibitor of Rac1 activity also blunted HO-1 protein expression. Moreover, inhibition of the NADPH oxidase by RNAi directed toward the 47-kd cytosolic subunit of Nox (p47phox) similarly abrogated HO-1 levels.

Conclusions: BCR-ABL1 expression up-regulated HO-1, a survival factor for CML cells. This up-regulation was more pronounced in blast crisis CML relative to early stage disease and was mediated by the NADPH oxidase components Rac1 and p47phox. The expression of p47phox was increased in BCR-ABL1-expressing cells.

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.26621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3297684PMC
July 2012
4 Reads

Publication Analysis

Top Keywords

nadph oxidase
28
bcr-abl1-expressing cells
12
specimens patients
12
blast crisis
12
inhibition nadph
12
patients cml
12
ho-1
10
cml
10
ho-1 expression
8
increased bcr-abl1-expressing
8
heme oxygenase
8
cml blast
8
oxidase
7
nadph
6
expression
6
marrow specimens
4
bone marrow
4
evaluated bone
4
cytosolic subunit
4
cml cell
4

Similar Publications