Cancer Research 2015-06-15

Targeting Mitochondria with Avocatin B Induces Selective Leukemia Cell Death.

Eric A Lee, Leonard Angka, Sarah-Grace Rota, Thomas Hanlon, Andrew Mitchell, Rose Hurren, Xiao Ming Wang, Marcela Gronda, Ezel Boyaci, Barbara Bojko, Mark Minden, Shrivani Sriskanthadevan, Alessandro Datti, Jeffery L Wrana, Andrea Edginton, Janusz Pawliszyn, Jamie W Joseph, Joe Quadrilatero, Aaron D Schimmer, Paul A Spagnuolo

Index: Cancer Res. 75 , 2478-88, (2015)

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Abstract

Treatment regimens for acute myeloid leukemia (AML) continue to offer weak clinical outcomes. Through a high-throughput cell-based screen, we identified avocatin B, a lipid derived from avocado fruit, as a novel compound with cytotoxic activity in AML. Avocatin B reduced human primary AML cell viability without effect on normal peripheral blood stem cells. Functional stem cell assays demonstrated selectivity toward AML progenitor and stem cells without effects on normal hematopoietic stem cells. Mechanistic investigations indicated that cytotoxicity relied on mitochondrial localization, as cells lacking functional mitochondria or CPT1, the enzyme that facilitates mitochondria lipid transport, were insensitive to avocatin B. Furthermore, avocatin B inhibited fatty acid oxidation and decreased NADPH levels, resulting in ROS-dependent leukemia cell death characterized by the release of mitochondrial proteins, apoptosis-inducing factor, and cytochrome c. This study reveals a novel strategy for selective leukemia cell eradication based on a specific difference in mitochondrial function.©2015 American Association for Cancer Research.