Abstract
Bcr-Abl kinase inhibitors are very effective drugs for treatment of chronic myelogenous leukemia (CML), but treatment options are limited and relatively ineffective for patients with de-novo or acquired resistance. The K562 human erythroleukemia cell line, derived from a pleural effusion during blast crisis of a CML patient, is very useful for studying hematopoietic differentiation because it undergoes differentiation and apoptosis in response to chemicals that propagate lipid-peroxidation. 4-hydroxynonenal (4-HNE), a reactive aldehyde produced from peroxidation of polyunsaturated fatty acids, is metabolized primarily by glutathione S-transferases (GSTs). 4-HNE causes differentiation, apoptosis and necrosis in K562 cells, but cannot be used as a drug for resistant CML because of its highly toxic nature. Present studies addressed the possibility of developing an alternative targeted treatment aimed at increasing intracellular 4-HNE through inhibition of GST. Because the major GST-isoenzymes in leukemia cells are also present in normal tissues, we explored the possibility of modulating cellular 4-HNE levels by inhibiting GST isozymes with high activity towards 4-HNE. Our studies identified the presence of the GSTO1 isoenzyme in K562 cells, demonstrated its activity towards 4-HNE, and showed that its depletion causes apoptosis, necrosis and differentiation of these cells. These effects of GSTO1 depletion appear to involve RUNX1 mediated transcriptional regulation of GM-CSF. These findings offer a new target for treatment of resistant CML.
Highlights
Bcr-Abl kinase inhibitors are very effective and non-toxic first line therapy for chronic myeloid leukemia (CML), but de-novo as well as acquired resistance occurs in 20-30% of patients for who therapeutic options are limited [1,2,3]
K562 cells express multiple glutathione S-transferases (GSTs) isoenzymes and modulate cell growth and apoptosis in K562 cells [11,18,19]. 4-HNE mediated effects on K562 may be due to effects on several signaling kinases (JNK, MAPK, Akt), apoptotic proteins (Bax, Bcl2) and transcription factors (Myc, Mad, GATA-1, AP-1) are known to be involved with K562 differentiation indicating that multiple simultaneous mechanisms may be operative, but the relative contribution of each or the molecular mechanisms through which 4-HNE exerts these effects are not known [20,21,22,23,24,25,26,27]
We have previously reported that K562 cells contain two quantitatively predominant cytosolic GST isoenzymes belonging to the P- and M-classes.A third low-abundance isoenzyme with pI 5.8 was identified and shown to be immunologically cross-reactive with alpha-class GSTs (GSTA) and displayed high specific activity towards 4-HNE, but its molecular identity could not be confirmed because of its low abundance [18]
Summary
Bcr-Abl kinase inhibitors are very effective and non-toxic first line therapy for chronic myeloid leukemia (CML), but de-novo as well as acquired resistance occurs in 20-30% of patients for who therapeutic options are limited [1,2,3]. GSTs are the rate-limiting enzyme of the mercapturic acid pathway and several GST-isoenzymes display differential catalytic activity against 4-HNE [8,9,10,11]. Because they metabolize numerous mutagenic compounds as well as chemotherapy drugs, GSTs play a major role in carcinogenesis and cancer drug-resistance [12,13,14,15]. K562 cells express multiple GST isoenzymes and modulate cell growth and apoptosis in K562 cells [11,18,19]. 4-HNE mediated effects on K562 may be due to effects on several signaling kinases (JNK, MAPK, Akt), apoptotic proteins (Bax, Bcl2) and transcription factors (Myc, Mad, GATA-1, AP-1) are known to be involved with K562 differentiation indicating that multiple simultaneous mechanisms may be operative, but the relative contribution of each or the molecular mechanisms through which 4-HNE exerts these effects are not known [20,21,22,23,24,25,26,27]
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