A potential role of fetal hemoglobin in the development of multidrug resistance
2012 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 427, no 3, 456-460 p.Article in journal (Refereed) Published
Our previous data from a human leukemic cell line made resistant to the nucleoside analog (NA) 9-beta-D-arabinofuranosylguanine (AraG) revealed a massive upregulation of fetal hemoglobin (HbF) genes and the ABCB1 gene coding for the multidrug resistance P-glycoprotein (P-gp). The expression of these genes is regulated through the same mechanisms, with activation of the p38-MAPK pathway and inhibition of methylation making transcription factors more accessible to activate these genes. We could show that AraG, as well as other NAs, and P-gp substrates could induce global DNA demethylation and induction of Hb gamma and P-gp both at the mRNA and protein expression level. We speculate that the expression of HbF prior to drug exposure or in drug-resistant cell lines is a strategy of the cancer to gain more oxygen, and thereby survival benefits. We also believe that P-gp may be induced in order to excrete Hb degradation products from the cells that would otherwise be toxic. By using Hb gamma siRNA and pharmacological inhibitors of HbF production we here present a possible relationship between HbF induction and multi-drug resistance in a human leukemia cell line model.
Place, publisher, year, edition, pages
Elsevier , 2012. Vol. 427, no 3, 456-460 p.
Multi-drug resistance, Fetal hemoglobin, Demethylation, Nucleoside analog
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-86656DOI: 10.1016/j.bbrc.2012.07.129ISI: 000311263200004OAI: oai:DiVA.org:liu-86656DiVA: diva2:580087
Funding Agencies|Swedish Cancer Foundation||County Council of Ostergotland||AFA insurance||2012-12-202012-12-202012-12-20