Abstract
Targeting cancer stem cells is of paramount importance in successfully preventing cancer relapse. Recently, in silico screening of public gene-expression datasets identified cyclooxygenase-derived cyclopentenone prostaglandins (CyPGs) as likely agents to target malignant stem cells. We show here that Δ(12)-PGJ(3), a novel and naturally produced CyPG from the dietary fish-oil ω-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA; 20:5) alleviates the development of leukemia in 2 well-studied murine models of leukemia. IP administration of Δ(12)-PGJ(3) to mice infected with Friend erythroleukemia virus or those expressing the chronic myelogenous leukemia oncoprotein BCR-ABL in the hematopoietic stem cell pool completely restored normal hematologic parameters, splenic histology, and enhanced survival. More importantly, Δ(12)-PGJ(3) selectively targeted leukemia stem cells (LSCs) for apoptosis in the spleen and BM. This treatment completely eradicated LSCs in vivo, as demonstrated by the inability of donor cells from treated mice to cause leukemia in secondary transplantations. Given the potency of ω-3 polyunsaturated fatty acid-derived CyPGs and the well-known refractoriness of LSCs to currently used clinical agents, Δ(12)-PGJ(3) may represent a new chemotherapeutic for leukemia that targets LSCs.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / drug effects*
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Ataxia Telangiectasia Mutated Proteins
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Blotting, Western
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Line
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Cell Line, Tumor
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Cell Survival / drug effects
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Cyclopentanes / chemistry
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Cyclopentanes / metabolism
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Cyclopentanes / pharmacology
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Dose-Response Relationship, Drug
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Fatty Acids, Omega-3 / chemistry
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Fatty Acids, Omega-3 / metabolism
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Fatty Acids, Omega-3 / pharmacology*
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Leukemia / drug therapy*
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Leukemia / metabolism
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Leukemia / pathology
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Leukemia, Erythroblastic, Acute / drug therapy
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Leukemia, Erythroblastic, Acute / metabolism
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Leukemia, Erythroblastic, Acute / pathology
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
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Macrophages / cytology
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Macrophages / drug effects
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Macrophages / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Molecular Structure
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Neoplastic Stem Cells / drug effects*
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology
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Prostaglandins / chemistry
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Prostaglandins / metabolism
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Prostaglandins / pharmacology*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Splenomegaly / pathology
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Splenomegaly / prevention & control
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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Cell Cycle Proteins
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Cyclopentanes
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DNA-Binding Proteins
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Fatty Acids, Omega-3
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Prostaglandins
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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delta12-prostaglandin J3
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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Protein Serine-Threonine Kinases
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cyclopentenone