Rational Design of a Parthenolide-based Drug Regimen That Selectively Eradicates Acute Myelogenous Leukemia Stem Cells.

Abstract

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.

• Authors: Shanshan Pei, Mohammad Minhajuddin, Angelo D'Alessandro, Travis Nemkov, Brett M Stevens, Biniam Adane, Nabilah Khan, Fred K Hagen, Vinod K Yadav, Subhajyoti De, John M Ashton, Kirk C Hansen, Jonathan A Gutman, Daniel A Pollyea, Peter A Crooks, Clayton Smith, Craig T Jordan
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 291 Issue 42 Pg. 21984-22000 (Oct 14 2016) ISSN: 1083-351X [Electronic] United States
• PMID: 27573247 (Publication Type: Journal Article)
• Copyright: © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• NF-E2-Related Factor 2
• NFE2L2 protein, human
• Neoplasm Proteins
• Sesquiterpenes
• parthenolide
• NADP
• temsirolimus
• Deoxyglucose
• Sirolimus

Topics

• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Deoxyglucose (pharmacology)
• Female
• Gene Expression Regulation, Leukemic (drug effects)
• Humans
• Leukemia, Myeloid, Acute (drug therapy, metabolism, pathology)
• Male
• NADP (biosynthesis)
• NF-E2-Related Factor 2 (metabolism)
• Neoplasm Proteins (metabolism)
• Neoplastic Stem Cells (metabolism, pathology)
• Sesquiterpenes (pharmacology)
• Sirolimus (analogs & derivatives, pharmacology)
• Up-Regulation (drug effects)