Targeting Aberrant Glutathione Metabolism to Eradicate Human Acute Myelogenous Leukemia Cells
| Autor: | Patricia Greninger, Jane L. Liesveld, Kevin P. Callahan, Shanshan Pei, Jeffrey Settleman, Cyril H. Benes, Cheryl Corbett, John M. Ashton, Michael W. Becker, Fred K. Hagen, Peter A. Crooks, Haobin Ye, Mohammad Minhajuddin, Zheng Li, Eleni D. Lagadinou, Joshua Munger, Kristen M. O'Dwyer, Lei Shi, Sarah J. Neering, Craig T. Jordan, Marlene Balys |
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| Rok vydání: | 2013 |
| Předmět: |
Male
GPX1 Glutamate-Cysteine Ligase CD34 Antigens CD34 macromolecular substances Biology medicine.disease_cause Biochemistry Myelogenous chemistry.chemical_compound Glutathione Peroxidase GPX1 hemic and lymphatic diseases Tumor Cells Cultured medicine Humans skin and connective tissue diseases Molecular Biology Glutathione Peroxidase Anti-Inflammatory Agents Non-Steroidal Dioxolanes Molecular Bases of Disease Cell Biology Glutathione medicine.disease Leukemia Myeloid Acute Oxidative Stress Leukemia GCLC chemistry Immunology Cancer research Female sense organs Stem cell Oxidation-Reduction Sesquiterpenes Oxidative stress |
| Zdroj: | Journal of Biological Chemistry. 288:33542-33558 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m113.511170 |
| Popis: | The development of strategies to eradicate primary human acute myelogenous leukemia (AML) cells is a major challenge to the leukemia research field. In particular, primitive leukemia cells, often termed leukemia stem cells, are typically refractory to many forms of therapy. To investigate improved strategies for targeting of human AML cells we compared the molecular mechanisms regulating oxidative state in primitive (CD34(+)) leukemic versus normal specimens. Our data indicate that CD34(+) AML cells have elevated expression of multiple glutathione pathway regulatory proteins, presumably as a mechanism to compensate for increased oxidative stress in leukemic cells. Consistent with this observation, CD34(+) AML cells have lower levels of reduced glutathione and increased levels of oxidized glutathione compared with normal CD34(+) cells. These findings led us to hypothesize that AML cells will be hypersensitive to inhibition of glutathione metabolism. To test this premise, we identified compounds such as parthenolide (PTL) or piperlongumine that induce almost complete glutathione depletion and severe cell death in CD34(+) AML cells. Importantly, these compounds only induce limited and transient glutathione depletion as well as significantly less toxicity in normal CD34(+) cells. We further determined that PTL perturbs glutathione homeostasis by a multifactorial mechanism, which includes inhibiting key glutathione metabolic enzymes (GCLC and GPX1), as well as direct depletion of glutathione. These findings demonstrate that primitive leukemia cells are uniquely sensitive to agents that target aberrant glutathione metabolism, an intrinsic property of primary human AML cells. |
| Databáze: | OpenAIRE |
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