Chemical genomic screening reveals synergism between parthenolide and inhibitors of the PI-3 kinase and mTOR pathways.

Abstract:

:We have previously shown that the plant-derived compound parthenolide (PTL) can impair the survival and leukemogenic activity of primary human acute myeloid leukemia (AML) stem cells. However, despite the activity of this agent, PTL also induces cellular protective responses that likely function to reduce its overall cytotoxicity. Thus, we sought to identify pharmacologic agents that enhance the antileukemic potential of PTL. Toward this goal, we used the gene expression signature of PTL to identify compounds that inhibit cytoprotective responses by performing chemical genomic screening of the Connectivity Map database. This screen identified compounds acting along the phosphatidylinositol 3-kinase and mammalian target of rapamycin pathways. Compared with single agent treatment, exposure of AML cells to the combination of PTL and phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitors significantly decreased viability of AML cells and reduced tumor burden in vitro and in murine xenotransplantation models. Taken together, our data show that rational drug combinations can be identified using chemical genomic screening strategies and that inhibition of cytoprotective functions can enhance the eradication of primary human AML cells.

journal_name

Blood

journal_title

Blood

authors

Hassane DC,Sen S,Minhajuddin M,Rossi RM,Corbett CA,Balys M,Wei L,Crooks PA,Guzman ML,Jordan CT

doi

10.1182/blood-2010-04-278044

subject

Has Abstract

pub_date

2010-12-23 00:00:00

pages

5983-90

issue

26

eissn

0006-4971

issn

1528-0020

pii

blood-2010-04-278044

journal_volume

116

pub_type

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