title: Hemin reduces cellular sensitivity to imatinib and anthracyclins via Nrf2.
abstract: Heme plays an important biomodulating role in various cell functions. In this study, we examined the effects of hemin on cellular sensitivity to imatinib and other anti-leukemia reagents. Hemin treatment of human BCR/ABL-positive KCL22 leukemia cells increased IC(50) values of imatinib, that is, the drug resistance, in a dose-dependent manner without any change in the BCR/ABL kinase activity. Imatinib-induced apoptosis was also suppressed by hemin treatment in KCL22 cells. Hemin treatment increased the activity of gamma-glutamylcysteine synthetase (gamma-GCS) light subunit gene promoter, which contains a Maf recognition element (MARE). Protein levels of gamma-GCS and heme oxygenase-1 (HO-1), two MARE-containing genes, were also increased after hemin treatment. Knockdown of Nrf2 expression by RNA interference largely abolished the effect of hemin on imatinib-treated cells, suggesting that Nrf2 recognition of MARE is essential for the hemin-mediated protective effect. Similar to hemin, treatment of cells with delta-aminolevulinic acid (delta-ALA), the obligatory heme precursor, also increased IC(50) values of imatinib. In contrast, inhibition of cellular heme synthesis by succinylacetone increased the sensitivity of cells to imatinib in two imatinib-resistant cell lines, KCL22/SR and KU812/SR. Hemin treatment also decreased the sensitivity of cells to four anthracyclins, daunorubicin, idarubicin, doxorubicin, and mitoxantrone, in BCR/ABL-negative leukemia U937 and THP-1 cells, as well as in KCL22 cells. These findings thus indicate that cellular heme level plays an important role in determining the sensitivity of cells to imatinib and certain other anti-leukemia drugs and that the effect of heme may be mediated via its ability to upregulate Nrf2 activity.
authors.affiliation: Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan. t-nagai@jichi.ac.jp
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nagai
authors.forename: Satoru
authors.initials: S
authors.lastname: Kikuchi
authors.forename: Ken
authors.initials: K
authors.lastname: Ohmine
authors.forename: Takuji
authors.initials: T
authors.lastname: Miyoshi
authors.forename: Makiko
authors.initials: M
authors.lastname: Nakamura
authors.forename: Takahito
authors.initials: T
authors.lastname: Kondo
authors.forename: Kazumichi
authors.initials: K
authors.lastname: Furuyama
authors.forename: Norio
authors.initials: N
authors.lastname: Komatsu
authors.forename: Keiya
authors.initials: K
authors.lastname: Ozawa
mesh_terms: D018943:Anthracyclines / Q000494:pharmacology*; D001549:Benzamides; D045744:Cell Line, Tumor; D004347:Drug Interactions; D004351:Drug Resistance; D006427:Hemin / Q000494:pharmacology*; D006801:Humans; D000068877:Imatinib Mesylate; D007938:Leukemia / Q000188:drug therapy / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018943:Anthracyclines; D001549:Benzamides; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D010879:Piperazines; D011743:Pyrimidines; D006427:Hemin; D000068877:Imatinib Mesylate