New lessons from an “old” drug: A proteomic study of anthracycline-induced apoptosis in acute myelogenous leukemia
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Anthracyclines have been first line drugs for more than 3 decades in the treatment of acute myelogenous leukemia (AML). Even though the mechanism of action of anthracyclines has been extensively studied over the years, large gaps remain in our understanding of why they act better than most other drugs and how they induce cancer cell death. The present study was undertaken to identify protein changes that could shed further light on how the anthracyclines induce and execute apoptosis. By this approach, we hoped to identify proteins or pathways of particular importance in AML cell death that in the future could be exploited as new drug-targets and lead to the development and use of less toxic or more efficient drugs than the anthracyclines. We also expected to reveal weaknesses in anthracycline actions that could explain why many patients in the end develop resistance to the drug. Targeting these weak points by other drugs could open new avenues for combination treatment. By using various proteomic approaches to identify cleavage, degradation or altered phosphorylation of proteins, we found that components associated with the Hsp90 multi-protein complex, clathrin-mediated endocytosis, and protein synthesis to be targeted in cells undergoing or about to undergo anthracycline-induced apoptosis. The Hsp90 complex was targeted through cleavage of its co-chaperone p23. The truncation or downregulation of components of the clathrin-dependent endocytic pathway were associated with decreased endocytosis and increased accumulation of surface receptors with cell death-modulating capability. We also found that anthracyclines induced the pre-apoptotic synthesis of presumed anti-apoptotic proteins. That the pre-apoptotic protein synthesis served a net survival role was suggested by the ability of protein synthesis inhibitors to enhance anthracycline-induced cell death. This was true both in cell culture and in animal models of AML. In conclusion, the Thesis contributes to the knowledge of how anthracyclines induce apoptosis by pinpointing new protein targets and pathways that are heavily modified not only in the executionphase, but also in the induction-phase of apoptosis. Based on our findings, we propose a novel anthracycline-based combination treatment regime for patients with AML that consists of an anthracycline and a protein synthesis inhibitor administered in the pre-apoptotic phase.
Paper I: Leukemia 18, Gausdal, G.; Gjertsen, B. T.; Fladmark, K. E.; Demol, H.; Vandekerckhove, J. and S. O. Døskeland, Caspase-dependent, geldanamycin-enhanced cleavage of co-chaperone p23 in leukemic apoptosis, pp. 1989–1996. Copyright 2004 Nature Publishing Group. All rights reserved. Abstract only. Full text not available in BORA due to publisher restrictions. The published version is available at: http://dx.doi.org/10.1038/sj.leu.2403508Paper II: Blood 111(5), Gausdal, Gro; Gjertsen, B. T; McCormack, Emmet; Van Damme, Petra; Hovland, Randi; Karlstad, Camilla; Bruserud, Øystein; Gevaert, Kris; Vandekerckhove, Joël and Stein Ove Døskeland, Abolition of stress-induced protein synthesis sensitizes leukemia cells to anthracycline-induced death, pp. 2866-2877. Copyright 2008 by American Society of Hematology. Abstract only. Full text not available in BORA due to publisher restrictions. The published version is available at: http://dx.doi.org/10.1182/blood-2007-07-103242Paper III: Gausdal, Gro; Skavland, Jørn; Gevaert, Kris; Vandekerckhove, Joël; Døskeland, Stein Ove and Bjørn Tore Gjertsen,(2007), Clathrin light chain is targeted by anthracyclines and results in blocked endocytosis and attenuated receptor mediated survival signaling in leukemia. Draft.