Targeting Mitochondria with Avocatin B Induces Selective Leukemia Cell Death

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Date

2015-06-15

Author

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

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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. (C) 2015 AACR.

Subject Keywords

Acute myeloid-leukemia, Cytochrome-c release, Fatty-acid oxidation, Adipose-tissue, Antileukemic activity, Liver glycogen, Serum-lipids, Stem-cells, Apoptosis, Inhibition

URI

https://hdl.handle.net/11511/47356

Journal

CANCER RESEARCH

DOI

https://doi.org/10.1158/0008-5472.can-14-2676

Collections

Department of Chemistry, Article

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Citation Formats

E. A. Lee et al., “Targeting Mitochondria with Avocatin B Induces Selective Leukemia Cell Death,” CANCER RESEARCH, pp. 2478–2488, 2015, Accessed: 00, 2020. [Online]. Available: https://hdl.handle.net/11511/47356.