title: 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: From the Division of Hematology and.
authors: Shanshan
authors: S
authors: Pei
authors: From the Division of Hematology and.
authors: Mohammad
authors: M
authors: Minhajuddin
authors: Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, Colorado 80045.
authors: Angelo
authors: A
authors: D'Alessandro
authors: Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, Colorado 80045.
authors: Travis
authors: T
authors: Nemkov
authors: From the Division of Hematology and.
authors: Brett M
authors: BM
authors: Stevens
authors: From the Division of Hematology and.
authors: Biniam
authors: B
authors: Adane
authors: From the Division of Hematology and.
authors: Nabilah
authors: N
authors: Khan
authors: Department of Biochemistry and Biophysics and.
authors: Fred K
authors: FK
authors: Hagen
authors: Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado 80045, and.
authors: Vinod K
authors: VK
authors: Yadav
authors: Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado 80045, and.
authors: Subhajyoti
authors: S
authors: De
authors: Department of Microbiology and Immunology, University of Rochester, Rochester, New York 14642.
authors: John M
authors: JM
authors: Ashton
authors: Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, Colorado 80045.
authors: Kirk C
authors: KC
authors: Hansen
authors: From the Division of Hematology and.
authors: Jonathan A
authors: JA
authors: Gutman
authors: From the Division of Hematology and.
authors: Daniel A
authors: DA
authors: Pollyea
authors: Department of Pharmaceutical Sciences, University of Arkansas, Little Rock, Arkansas 72205.
authors: Peter A
authors: PA
authors: Crooks
authors: From the Division of Hematology and.
authors: Clayton
authors: C
authors: Smith
authors: From the Division of Hematology and craig.jordan@ucdenver.edu.
authors: Craig T
authors: CT
authors: Jordan
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D003847:Deoxyglucose / Q000494:pharmacology; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009249:NADP / Q000096:biosynthesis; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D012717:Sesquiterpenes / Q000494:pharmacology; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009363:Neoplasm Proteins; D012717:Sesquiterpenes; C002669:parthenolide; D009249:NADP; C401859:temsirolimus; D003847:Deoxyglucose; D020123:Sirolimus
keywords: 2-deoxyglucose; anticancer drug; drug combination; drug development; drug resistance; endoplasmic reticulum stress (ER stress); leukemia; oxidative stress; parthenolide; temsirolimus