Hemin counteracts the repression of Bcl-2 and NrF2 genes and the cell killing induced by imatinib in human Bcr-Abl(+) CML cells.
Imatinib is a targeted selective inhibitor of chimaeric Bcr-Abl tyrosine kinase developed for effective therapy of chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL) patients. Unfortunately, evidence now exists to indicate that a portion of such patients treated with imatinib acquire resistance and subsequently relapse. To understand the heterogeneous basis of imatinib resistance, we have investigated the possible mechanism(s) via which hemin, a key regulator of hematopoiesis that is converted to heme intracellularly, renders CML cells less susceptible to imatinib. Hemin at 30-90 aM protected a substantial proportion (>40%) of human Bcr-Abl(+) CML cells (K-562 and KU-812) from imatinib-induced cell killing by increasing the imatinib IC50 value, reducing DNA damage, and promoting erythroid differentiation. RT-PCR assessment of RNA transcripts encoded by human GAPDH, Ggamma-globin, Bcr-Abl, HO-2, Hpr-6, CEBPa, Bcl-2a, Bcl-2b, and Nrf2 genes revealed that hemin selectively counteracted the repression of antiapoptotic Bcl-2a, Bcl-2b, and Nrf2 genes in imatinib-treated cells. These genes are markedly repressed by imatinib alone in human K-562 CML cells. Hemin, however, had no detectable effect on the expression of the Bcr-Abl gene. Moreover, inhibition of de novo heme biosynthesis by succinyl-acetone enhanced the killing effect of imatinib. These data clearly indicate that: (a) cellular heme resulted from de novo biosynthesis and hemin uptake alters the developmental stage of human Bcr-Abl(+) CML cells and their susceptibility to imatinib; (b) cellular heme counteracts the ability of imatinib to repress Bcl-2 and Nrf2 gene expression; and (c) inhibitors of de novo biosynthesis can be developed and combined with imatinib to enhance its antileukemic activity.
Bonovolias
Ioannis D
ID
Laboratory of Pharmacology, Department of Pharmaceutical Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.
Tsiftsoglou
Asterios S
AS
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004249:DNA Damage; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D019254:Genes, bcl-2; D006427:Hemin / Q000494:pharmacology*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001549:Benzamides; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D010879:Piperazines; D011743:Pyrimidines; D006427:Hemin; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl