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Rational Design of a Parthenolide-based Drug Regimen That Selectively Eradicates Acute Myelogenous Leukemia Stem
Shanshan Pei1, Mohammad Minhajuddin1, Angelo D'Alessandro2
1From the Division of Hematology and.
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.
Insights
This study presents a rational drug combination strategy targeting acute myelogenous leukemia (AML) stem cells. The developed regimen selectively eradicates AML stem cells while sparing normal stem cells.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Multidrug cancer therapies often lack rigorous scientific design, relying on empirical data.
- Targeting cancer stem cells is crucial for effective leukemia treatment.
- Acute myelogenous leukemia (AML) stem cells possess unique redox balance mechanisms.
Purpose of the Study:
- To rationally design a combination drug regimen for selective targeting of human AML stem cells.
- To identify agents that inhibit compensatory mechanisms induced by initial treatment.
- To enhance the eradication of AML cells through a synergistic drug approach.
Main Methods:
- Utilized parthenolide as a starting agent targeting AML cell redox balance.
- Employed proteomic, genomic, and metabolomic analyses to understand cellular responses.
- Identified 2-deoxyglucose and temsirolimus to block compensatory pathways.
Main Results:
- Parthenolide treatment up-regulates NADPH production and activates the Nrf2 oxidative stress pathway.
- The combination of parthenolide, 2-deoxyglucose, and temsirolimus (PDT) effectively targets AML stem cells.
- The PDT regimen shows minimal impact on normal stem cells, indicating selectivity.
Conclusions:
- A comprehensive, science-based strategy for designing combination anticancer drug regimens was developed.
- The PDT regimen offers a potent and selective approach for targeting AML stem cells.
- This approach provides a framework for developing targeted therapies for other cancers.
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