| Title | Kinetic Analysis of hemin-induced protection of human erythroleukemia K-562 cells from the apoptotic effect of Gleevec | |
| Authors | Ioannis D. Bonovolias and Asterios S. Tsiftsoglou
Laboratory of Pharmacology, Department of Pharmaceutical Sciences, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece |
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| Citation | Bonovolias, I.D., Tsiftsoglou, A.S.: Kinetic Analysis of hemin-induced protection of human erythroleukemia K-562 cells from the apoptotic effect of Gleevec, Epitheorese Klin. Farmakol. Farmakokinet. 20(2): 78-80 (2006) | |
| Publication Date | Accepted for publication: 19-20 May 2006 | |
| Full Text Language | English | |
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| Keywords | Gleevec (imatinib mesylate), protoporphyrin-IX, hemin-induced protection, human erythroleukemia K-562 cells. | |
| Other Terms | review article | |
| Summary | Gleevec (Imatinib mesylate) is an innovative targeted selective inhibitor of Bcr-Abl chimeric tyrosine kinase developed and used for the therapy of Chronic Myelogenous Leukemia (CML). Unfortunately, resistance to Gleevec has been recorded to occur in several occasions. The precise mechanism(s) of Gleevec-induced resistance are not clear, although evidence exists to indicate that mutations in the Bcr-Abl gene may be responsible. Most recently, we observed that Hemin (oxidized iron protoporphyrin-IX), a hematopoietic cell growth and differ- entiation regulator, prevents Gleevec to kill human erythroleukemia K-562 cells in culture. In the present study, we extended these observations and explored the Hemin-induced resistance to Gleevec kinetically in order to demonstrate the mechanism of this phenomenon. Human erythroleukemia K-562 cells used as a suitable model for CML, were exposed to either Gleevec (10-6 M) or Hemin (90 µM) alone separately for different time intervals (0 – 96 hours) and then treated in the absence or presence of Gleevec. Cells co-exposed to both agents simultaneously served as control experiment. Cell growth and viability were measured at each time point. In additional, cells treated under various conditions with Gleevec and Hemin were analyzed by flow-cytometric analysis. Our data indicate the following: (a) Gleevec needs at least 12-24 hours to kill human erythroleukemia K-562 cells, that is at least one cell cycle. (b) Hemin is needed to be present continuously in order to prevent human erythroleukemia K- 562 cells from apoptosis induced by Gleevec. Hemin was able to rescue human erythroleukemia K-562 cells from Gleevec when added within the first 24 hours but not cells pre-treated with Gleevec longer. These findings indicate that Hemin antagonizes the apoptotic effect of Gleevec. It is likely that this effect of Hemin contributes to the survival and outgrowth of leukemia cells in the presence of Gleevec during treatment of CML.
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| References | 1. Tsiftsoglou A.S., Tsamadou A.Ι., Papadopoulou L.C.: Heme as key regulator of major mammalian cellular functions: Molecular, cellular and pharmacological aspects. Pharmacol. Therap. (in Press) (2006)
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Online ISSN 1011-6575
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