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

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

doi:10.1074/jbc.m116.750653

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.

Highlights

Multidrug approaches to cancer therapy are common, few strategies are based on rigorous scientific principles
We demonstrate that the parthenolide, 2-deoxyglucose, temsirolimus regimen is a potent means of targeting acute myelogenous leukemia (AML) stem cells but has little to no effect on normal stem cells
By integrating results from these omic studies along with our previous reports, we discovered that PTL directly modulates several components of AML redox balance and induces strong activation of the Nrf2-mediated oxidative stress response as well as up-regulation of the pentose phosphate pathway (PPP), both of which are thought to be compensatory mechanisms that are employed by AML cells in an effort to survive the PTL insult

Summary

Introduction

Multidrug approaches to cancer therapy are common, few strategies are based on rigorous scientific principles. 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. To enhance the design of combination regimens, we sought to draw upon advanced methods of global cell analysis that allow comprehensive studies of genomic, proteomic, and metabolomic properties Such strategies have become prevalent in recent years and are routinely used in most types of biological research. The studies described here were designed to identify and target fundamental conserved components of AML stem cell biology

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Conclusion