Abstract
Resistance toward imatinib (IM) and other BCR/ABL tyrosine kinase inhibitors remains troublesome in the treatment of advanced stage chronic myeloid leukemia (CML). The aim of this study was to estimate the reversal effects of down-regulation of Na(+)/H(+) exchanger 1 (NHE1) on the chemoresistance of BCR-ABL-positive leukemia patients' cells and cell lines. After treatment with the specific NHE1 inhibitor cariporide to decrease intracellular pH (pHi), the heme oxygenase-1 (HO-1) levels of the K562R cell line and cells from IM-insensitive CML patients decreased. HO-1, as a Bcr/Abl-dependent survival molecule in CML cells, is important for the resistance to tyrosine kinase inhibitors in patients with newly diagnosed CML or IM-resistant CML. Silencing PKC-β and Nrf-2 or treatment with inhibitors of p38 pathways obviously blocked NHE1-induced HO-1 expression. Furthermore, treatment with HO-1 or p38 inhibitor plus IM increased the apoptosis of the K562R cell line and IM-insensitive CML patients' cells. Inhibiting HO-1 enhanced the activation of caspase-3 and poly(ADP-ribose) polymerase-1. Hence, the results support the anti-apoptotic role of HO-1 induced by NHE1 in the K562R cell line and IM-insensitive CML patients and provide a mechanism by which inducing HO-1 expression via the PKC-β/p38-MAPK pathway may promote tumor resistance to oxidative stress.
Keywords:
Na+/H+ ion exchanger 1; chronic myelogenous leukemia (CML); drug resistance; heme oxygenase; imatinib resistance; p38 MAPK; p38/mitogen-activated protein kinase; protein kinase C (PKC).
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
Publication types
-
Clinical Trial
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adult
-
Aged
-
Apoptosis / drug effects
-
Apoptosis / genetics
-
Benzamides / pharmacology*
-
Cation Transport Proteins / genetics
-
Cation Transport Proteins / metabolism*
-
Drug Resistance, Neoplasm / drug effects*
-
Drug Resistance, Neoplasm / genetics
-
Enzyme Induction / drug effects
-
Enzyme Induction / genetics
-
Female
-
Gene Expression Regulation, Leukemic
-
Heme Oxygenase-1 / biosynthesis*
-
Heme Oxygenase-1 / genetics
-
Humans
-
Imatinib Mesylate
-
K562 Cells
-
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
-
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
-
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
-
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
-
MAP Kinase Signaling System / drug effects
-
MAP Kinase Signaling System / genetics
-
Male
-
Middle Aged
-
NF-E2-Related Factor 2 / genetics
-
NF-E2-Related Factor 2 / metabolism
-
Neoplasm Proteins / antagonists & inhibitors
-
Neoplasm Proteins / genetics
-
Neoplasm Proteins / metabolism*
-
Oxidative Stress / drug effects
-
Oxidative Stress / genetics
-
Piperazines / pharmacology*
-
Protein Kinase C beta / antagonists & inhibitors
-
Protein Kinase C beta / genetics
-
Protein Kinase C beta / metabolism
-
Protein Kinase Inhibitors / pharmacology*
-
Pyrimidines / pharmacology*
-
Sodium-Hydrogen Exchanger 1
-
Sodium-Hydrogen Exchangers / genetics
-
Sodium-Hydrogen Exchangers / metabolism*
Substances
-
Benzamides
-
Cation Transport Proteins
-
NF-E2-Related Factor 2
-
NFE2L2 protein, human
-
Neoplasm Proteins
-
Piperazines
-
Protein Kinase Inhibitors
-
Pyrimidines
-
SLC9A1 protein, human
-
Sodium-Hydrogen Exchanger 1
-
Sodium-Hydrogen Exchangers
-
Imatinib Mesylate
-
HMOX1 protein, human
-
Heme Oxygenase-1
-
PRKCB protein, human
-
Protein Kinase C beta