title: Targeting Mitochondria with Avocatin B Induces Selective Leukemia Cell Death.
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.
authors.affiliation: School of Pharmacy, University of Waterloo, Kitchener, Ontario, Canada.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Lee
authors.affiliation: School of Pharmacy, University of Waterloo, Kitchener, Ontario, Canada.
authors.forename: Leonard
authors.initials: L
authors.lastname: Angka
authors.affiliation: School of Pharmacy, University of Waterloo, Kitchener, Ontario, Canada.
authors.forename: Sarah-Grace
authors.initials: SG
authors.lastname: Rota
authors.affiliation: School of Pharmacy, University of Waterloo, Kitchener, Ontario, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hanlon
authors.affiliation: Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Mitchell
authors.affiliation: Princess Margaret Cancer Center, Ontario Cancer Institute, Toronto, Ontario, Canada.
authors.forename: Rose
authors.initials: R
authors.lastname: Hurren
authors.affiliation: Princess Margaret Cancer Center, Ontario Cancer Institute, Toronto, Ontario, Canada.
authors.forename: Xiao Ming
authors.initials: XM
authors.lastname: Wang
authors.affiliation: Princess Margaret Cancer Center, Ontario Cancer Institute, Toronto, Ontario, Canada.
authors.forename: Marcela
authors.initials: M
authors.lastname: Gronda
authors.affiliation: Department of Chemistry, University of Waterloo, Waterloo, Ontario, Canada.
authors.forename: Ezel
authors.initials: E
authors.lastname: Boyaci
authors.affiliation: Department of Chemistry, University of Waterloo, Waterloo, Ontario, Canada.
authors.forename: Barbara
authors.initials: B
authors.lastname: Bojko
authors.affiliation: Princess Margaret Cancer Center, Ontario Cancer Institute, Toronto, Ontario, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Minden
authors.affiliation: Princess Margaret Cancer Center, Ontario Cancer Institute, Toronto, Ontario, Canada.
authors.forename: Shrivani
authors.initials: S
authors.lastname: Sriskanthadevan
authors.affiliation: 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.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Datti
authors.affiliation: SMART Laboratory for High-Throughput Screening Programs, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Wrana
authors.affiliation: School of Pharmacy, University of Waterloo, Kitchener, Ontario, Canada.
authors.forename: Andrea
authors.initials: A
authors.lastname: Edginton
authors.affiliation: Department of Chemistry, University of Waterloo, Waterloo, Ontario, Canada.
authors.forename: Janusz
authors.initials: J
authors.lastname: Pawliszyn
authors.affiliation: School of Pharmacy, University of Waterloo, Kitchener, Ontario, Canada.
authors.forename: Jamie W
authors.initials: JW
authors.lastname: Joseph
authors.affiliation: Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada.
authors.forename: Joe
authors.initials: J
authors.lastname: Quadrilatero
authors.affiliation: Princess Margaret Cancer Center, Ontario Cancer Institute, Toronto, Ontario, Canada.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schimmer
authors.affiliation: School of Pharmacy, University of Waterloo, Kitchener, Ontario, Canada. paul.spagnuolo@uwaterloo.ca.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Spagnuolo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002853:Chromatography, Liquid / Q000379:methods; D005638:Fruit / Q000737:chemistry; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D027421:Persea / Q000737:chemistry; D010936:Plant Extracts / Q000494:pharmacology*; D010938:Plant Oils / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D010936:Plant Extracts; D010938:Plant Oils; D017382:Reactive Oxygen Species