Rational Design of a Parthenolide-based Drug Regimen That Selectively Eradicates Acute Myelogenous Leukemia Stem Cells
| Autor: | Clayton A. Smith, Daniel A. Pollyea, Craig T. Jordan, Mohammad Minhajuddin, Kirk C. Hansen, Fred K. Hagen, Subhajyoti De, Jonathan A. Gutman, John M. Ashton, Vinod Kumar Yadav, Travis Nemkov, Shanshan Pei, Biniam Adane, Brett M. Stevens, Angelo D'Alessandro, Nabilah Khan, Peter A. Crooks |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Myeloid NF-E2-Related Factor 2 Deoxyglucose Pharmacology Biology Biochemistry 03 medical and health sciences chemistry.chemical_compound Myelogenous Antineoplastic Combined Chemotherapy Protocols medicine Humans Parthenolide Molecular Biology Sirolimus Gene Expression Regulation Leukemic Molecular Bases of Disease Cell Biology medicine.disease Temsirolimus Neoplasm Proteins Up-Regulation Leukemia Myeloid Acute Regimen Leukemia 030104 developmental biology medicine.anatomical_structure chemistry Drug development Neoplastic Stem Cells Female Additions and Corrections Stem cell Sesquiterpenes NADP medicine.drug |
| Zdroj: | Journal of Biological Chemistry. 291:21984-22000 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m116.750653 |
| Popis: | Although multidrug approaches to cancer therapy are common, few strategies are based on rigorous scientific principles. Rather, drug combinations are largely dictated by empirical or clinical parameters. In the present study we developed a strategy for rational design of a regimen that selectively targets human acute myelogenous leukemia (AML) stem cells. As a starting point, we used parthenolide, an agent shown to target critical mechanisms of redox balance in primary AML cells. Next, using proteomic, genomic, and metabolomic methods, we determined that treatment with parthenolide leads to induction of compensatory mechanisms that include up-regulated NADPH production via the pentose phosphate pathway as well as activation of the Nrf2-mediated oxidative stress response pathway. Using this knowledge we identified 2-deoxyglucose and temsirolimus as agents that can be added to a parthenolide regimen as a means to inhibit such compensatory events and thereby further enhance eradication of AML cells. We demonstrate that the parthenolide, 2-deoxyglucose, temsirolimus (termed PDT) regimen is a potent means of targeting AML stem cells but has little to no effect on normal stem cells. Taken together our findings illustrate a comprehensive approach to designing combination anticancer drug regimens. |
| Databáze: | OpenAIRE |
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