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Cancer Res. 2015 Jun 15;75(12):2478-88. doi: 10.1158/0008-5472.CAN-14-2676.

Targeting Mitochondria with Avocatin B Induces Selective Leukemia Cell Death.

Author information

1
School of Pharmacy, University of Waterloo, Kitchener, Ontario, Canada.
2
Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada.
3
Princess Margaret Cancer Center, Ontario Cancer Institute, Toronto, Ontario, Canada.
4
Department of Chemistry, University of Waterloo, Waterloo, Ontario, Canada.
5
SMART Laboratory for High-Throughput Screening Programs, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. Department of Agricultural, Food and Environmental Sciences, University of Perugia, Perugia, Italy.
6
SMART Laboratory for High-Throughput Screening Programs, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
7
School of Pharmacy, University of Waterloo, Kitchener, Ontario, Canada. paul.spagnuolo@uwaterloo.ca.

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.

PMID:
26077472
DOI:
10.1158/0008-5472.CAN-14-2676
[Indexed for MEDLINE]
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