Targeting Mitochondria with Avocatin B Induces Selective Leukemia Cell Death

Autor: Eric A. Lee, Janusz Pawliszyn, Rose Hurren, Sarah-Grace Rota, Shrivani Sriskanthadevan, Joe Quadrilatero, Thomas Hanlon, Marcela Gronda, Ezel Boyacı, Paul A. Spagnuolo, Jamie W. Joseph, Alessandro Datti, Jeffery L. Wrana, Andrew S. Mitchell, Aaron D. Schimmer, Xiaoming Wang, Barbara Bojko, Mark D. Minden, Andrea N. Edginton, Leonard Angka
Rok vydání: 2015
Předmět:
CYTOCHROME-C RELEASE
Cancer Research
FATTY-ACID OXIDATION
Cell
INHIBITION
Apoptosis
ACUTE MYELOID-LEUKEMIA
Biology
Mitochondrion
Mass Spectrometry
Mice
Cancer stem cell
hemic and lymphatic diseases
medicine
Cytotoxic T cell
Animals
Humans
Plant Oils
LIVER GLYCOGEN
Cell Death
Persea
Plant Extracts
Myeloid leukemia
medicine.disease
Xenograft Model Antitumor Assays
Cell biology
High-Throughput Screening Assays
Mitochondria
Leukemia
Haematopoiesis
Leukemia
Myeloid
Acute
ADIPOSE-TISSUE
medicine.anatomical_structure
Oncology
Fruit
SERUM-LIPIDS
ACUTE MYELOID-LEUKEMIA
CYTOCHROME-C RELEASE
FATTY-ACID OXIDATION
ADIPOSE-TISSUE
ANTILEUKEMIC ACTIVITY
LIVER GLYCOGEN
SERUM-LIPIDS
STEM-CELLS
APOPTOSIS
INHIBITION
Stem cell
Reactive Oxygen Species
ANTILEUKEMIC ACTIVITY
STEM-CELLS
Oxidation-Reduction
Chromatography
Liquid
Zdroj: Cancer research. 75(12)
ISSN: 1538-7445
Popis: 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. Cancer Res; 75(12); 2478–88. ©2015 AACR.
Databáze: OpenAIRE
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