ABC transporter expression in hematopoietic stem cells and the role in AML drug resistance

ATP-binding cassette (ABC) transporters are known to play an important role in human physiology, toxicology, pharmacology, and numerous disorders including acute myeloid leukemia (AML). In AML only a few cells have properties allowing for ongoing proliferation and for expansion of this malignant disorder. These very primitive cells, referred to as leukemic stem cells, reside mostly in a quiescent cell cycle state. These cells have the capacity of self-renewal and are likely characterized by a high expression of a number of ABC transporters. In addition, over-expression of certain ABC transporters in leukemic cells has been associated with poor treatment outcome in AML patients. Therefore, to be able to improve diagnostics and therapies for AML patients, it may be important to better characterize this quiescent stem cell population. Particularly knowledge of the biology of highly expressed ABC transporters in these primitive leukemic cells might provide new insights to improve therapeutic options. This review provides an overview about ABC transporters and AML in general and particularly of the ABC transporters involved in multidrug resistance and cholesterol metabolism in primitive normal and leukemic cells. (C) 2007 Elsevier Ireland Ltd. All rights reserved

Combining Simvastatin with the Farnesyltransferase Inhibitor Tipifarnib Results in an Enhanced Cytotoxic Effect in a Subset of Primary CD34(+) Acute Myeloid Leukemia Samples

Purpose: To show whether the inhibitory effects of the cholesterol synthesis inhibitor simvastatin on human CD34(+) acute myeloid leukemia (AML) cells can be further promoted by combining it with the farnesyltransferase inhibitor tipifarnib. Experimental Design: Normal CD34(+), AML CD34(+), and CD34(-) sorted subfractions, and AML cell lines (TF-1 and KG1A) were exposed to simvastatin and tipifarnib. Results: Both simvastatin and tipifarnib showed a cytotoxic effect on AML cell lines, which was additive when used in combination. In primary sorted CD34(+) AML cells, a heterogeneous response pattern was observed upon treatment with simvastatin when analyzing cell survival. A group of normal (n = 12) and abnormal (n = 10) responders were identified within the AML CD34(+) subfraction when compared with normal CD34(+) cells. This distinction was not observed within the AML CD34(-) cell fraction. When the CD34(+) AML cells were exposed to simvastatin and tipifarnib, a significant enhanced inhibitory effect was shown exclusively in the normal AML responder group, whereas the AML CD34(-) cell fractions all showed an enhanced inhibitory effect. The observed heterogeneity in AML responsiveness could not be explained by differences in effects on cholesterol metabolism genes or extracellular signal-regulated kinase phosphorylation in response to simvastatin and tipifarnib treatment. Conclusion: The results suggest that combined treatment with statins and farnesyltransferase inhibitors may be beneficial for a subset of AML patients that can be defined by studying the AML CD34(+) fraction

Variability in responsiveness to lovastatin of the primitive CD34(+) AML subfraction compared to normal CD34(+) cells

International audienceIn the present study, we questioned whether the cholesterol synthesis inhibitor lovastatin potentiates the cytotoxicity of chemotherapeutic agents in the primitive CD34 subpopulation of acute myeloid leukemia (AML) cells. AML mononuclear cells ( = 17) were sorted in CD34 and CD34 fractions and compared to normal CD34 cells ( = 7). The percentage of surviving cells upon exposure to lovastatin (25–100 μM) and/or chemotherapeutics (cytarabin or daunorubicin) was determined with a luminescent cell viability assay. The results demonstrate that the primitive CD34 subpopulation of normal and AML cells displayed a higher sensitivity to lovastatin than the more mature CD34 subpopulation. The combination of lovastatin and chemotherapeutics resulted in a more pronounced inhibitory effect on both subpopulations. In contrast to the homogeneous results in normal CD34 cells, a distinct heterogeneity in lovastatin sensitivity was found in AML samples. Therefore, a group of normal ( = 11) and abnormal ( = 6) responders were identified based on a reduced or increased cell survival compared to normal CD34 cells. This distinction was not only observed in the CD34 AML subfraction but also in CD34CD38AML cells. In the abnormal responder group, 50% of patients presented with unfavorable cytogenetics and significant higher peripheral blast cell counts, which coincided with poor treatment results. In summary, the findings indicate that the primitive subfraction of CD34 AML cells is in the majority of cases affected by lovastatin treatment, which is potentiated when combined with chemotherapeutics. Heterogeneity of the response observed in AML patients allowed identification of a subgroup with poor prognosis