Chemopreventive Effects of Dietary Eicosapentaenoic Acid Supplementation in Experimental Myeloid Leukemia.
Current therapies for treatment of myeloid leukemia do not eliminate leukemia stem cells (LSC), leading to disease relapse. In this study, we supplemented mice with eicosapentaenoic acid (EPA, C20:5), a polyunsaturated omega-3 fatty acid, at pharmacologic levels, to examine whether the endogenous metabolite, cyclopentenone prostaglandin delta-12 PGJ3 (Δ(12)-PGJ3), was effective in targeting LSCs in experimental leukemia. EPA supplementation for 8 weeks resulted in enhanced endogenous production of Δ(12)-PGJ3 that was blocked by indomethacin, a cyclooxygenase (COX) inhibitor. Using a murine model of chronic myelogenous leukemia (CML) induced by bone marrow transplantation of BCR-ABL-expressing hematopoietic stem cells, mice supplemented with EPA showed a decrease in the LSC population, and reduced splenomegaly and leukocytosis, when compared with mice on an oleic acid diet. Supplementation of CML mice carrying the T315I mutation (in BCR-ABL) with EPA resulted in a similar effect. Indomethacin blocked the EPA effect and increased the severity of BCR-ABL-induced CML and decreased apoptosis. Δ(12)-PGJ3 rescued indomethacin-treated BCR-ABL mice and decreased LSCs. Inhibition of hematopoietic-prostaglandin D synthase (H-PGDS) by HQL-79 in EPA-supplemented CML mice also blocked the effect of EPA. In addition, EPA supplementation was effective in a murine model of acute myeloid leukemia. EPA-supplemented mice exhibited a decrease in leukemia burden and a decrease in the LSC colony-forming unit (LSC-CFU). The decrease in LSCs was confirmed through serial transplantation assays in all disease models. The results support a chemopreventive role for EPA in myeloid leukemia, which is dependent on the ability to efficiently convert EPA to endogenous COX-derived prostanoids, including Δ(12)-PGJ3.
Immunology and Infectious Diseases Graduate Program, The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania. Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania.
Emily R
ER
Finch
Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania.
Avinash K
AK
Kudva
Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania.
Michael D
MD
Quickel
Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania.
Laura L
LL
Goodfield
Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania.
Mary J
MJ
Kennett
Department of Nutrition, University of Tennessee, Knoxville, Tennesee.
Jay
J
Whelan
Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania. ksp@psu.edu rfp5@psu.edu.
Robert F
RF
Paulson
Center for Molecular Immunology and Infectious Disease and Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania. ksp@psu.edu rfp5@psu.edu.
K Sandeep
KS
Prabhu
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002853:Chromatography, Liquid; D019587:Dietary Supplements; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D005434:Flow Cytometry; D057809:HEK293 Cells; D006801:Humans; D020287:In Situ Nick-End Labeling; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D053719:Tandem Mass Spectrometry; D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays
D016588:Anticarcinogenic Agents; D015118:Eicosapentaenoic Acid