Dataset Information

?12-prostaglandin J3, an omega-3 fatty acid-derived metabolite, selectively ablates leukemia stem cells in mice.

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 ?(12)-PGJ(3), a novel and naturally produced CyPG from the dietary fish-oil ?-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 ?(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, ?(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 ?-3 polyunsaturated fatty acid-derived CyPGs and the well-known refractoriness of LSCs to currently used clinical agents, ?(12)-PGJ(3) may represent a new chemotherapeutic for leukemia that targets LSCs.

SUBMITTER: Hegde S

PROVIDER: S-EPMC3245211 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Δ12-prostaglandin J3, an omega-3 fatty acid-derived metabolite, selectively ablates leukemia stem cells in mice.

Hegde Shailaja S Kaushal Naveen N Ravindra Kodihalli C KC Chiaro Christopher C Hafer Kelsey T KT Gandhi Ujjawal H UH Thompson Jerry T JT van den Heuvel John P JP Kennett Mary J MJ Hankey Pamela P Paulson Robert F RF Prabhu K Sandeep KS

Blood 20111003 26

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 ...[more]

PMID: 21967980

Similar Datasets

Project description:Previous studies have demonstrated the ability of an eicosapentaenoic acid (EPA)-derived endogenous cyclopentenone prostaglandin (CyPG) metabolite, ?(12)-PGJ3, to selectively target leukemic stem cells, but not the normal hematopoietic stems cells, in in vitro and in vivo models of chronic myelogenous leukemia (CML). Here we evaluated the stability, bioavailability, and hypersensitivity of ?(12)-PGJ3. The stability of ?(12)-PGJ3 was evaluated under simulated conditions using artificial gastric and intestinal juice. The bioavailability of ?(12)-PGJ3 in systemic circulation was demonstrated upon intraperitoneal injection into mice by LC-MS/MS. ?(12)-PGJ3 being a downstream metabolite of PGD3 was tested in vitro using primary mouse bone marrow-derived mast cells (BMMCs) and in vivo mouse models for airway hypersensitivity. ZK118182, a synthetic PG analog with potent PGD2 receptor (DP)-agonist activity and a drug candidate in current clinical trials, was used for toxicological comparison. ?(12)-PGJ3 was relatively more stable in simulated gastric juice than in simulated intestinal juice that followed first-order kinetics of degradation. Intraperitoneal injection into mice revealed that ?(12)-PGJ3 was bioavailable and well absorbed into systemic circulation with a Cmax of 263 µg/L at 12 h. Treatment of BMMCs with ZK118182 for 12 h resulted in increased production of histamine, while ?(12)-PGJ3 did not induce degranulation in BMMCs nor increase histamine. In addition, in vivo testing for hypersensitivity in mice showed that ZK118182 induces higher airways hyperresponsiveness when compared ?(12)-PGJ3 and/or PBS control. Based on the stability studies, our data indicates that intraperitoneal route of administration of ?(12)-PGJ3 was favorable than oral administration to achieve effective pharmacological levels in the plasma against leukemia. ?(12)-PGJ3 failed to increase histamine and IL-4 in BMMCs, which is in agreement with reduced airway hyperresponsiveness in mice. In summary, our studies suggest ?(12)-PGJ3 to be a promising bioactive metabolite for further evaluation as a potential drug candidate for treating CML.

Project description:BackgroundThe intestinal microbiome is an important determinant of inflammatory balance in the colon that may affect response to dietary agents.ObjectiveThis is a secondary analysis of a clinical trial, the Fish Oil Study, to determine whether interindividual differences in colonic bacteria are associated with variability in the reduction of colonic prostaglandin E2 (PGE2) concentrations after personalized supplementation with ω-3 (n-3) fatty acids.MethodsForty-seven healthy adults (17 men, 30 women, ages 26-75 y) provided biopsy samples of colonic mucosa and luminal stool brushings before and after personalized ω-3 fatty acid supplementation that was based on blood fatty acid responses. Samples were analyzed using 16S ribosomal RNA sequencing. The data analyses focused on changes in bacterial community diversity. Linear regression was used to evaluate factors that predict a reduction in colonic PGE2.ResultsAt baseline, increased bacterial diversity, as measured by the Shannon and Inverse Simpson indexes in both biopsy and luminal brushing samples, was positively correlated with dietary fiber intakes and negatively correlated with fat intakes. Dietary supplementation with ω-3 fatty acids increased the Yue and Clayton community dis-similarity index between the microbiome in luminal brushings and colon biopsy samples post-supplementation (P = 0.015). In addition, there was a small group of individuals with relatively high Prevotella abundance who were resistant to the anti-inflammatory effects of ω-3 fatty acid supplementation. In linear regression analyses, increases in diversity of the bacteria in the luminal brushing samples, but not in the biopsy samples, were significant predictors of lower colonic PGE2 concentrations post-supplementation in models that included baseline PGE2, baseline body mass index, and changes in colonic eicosapentaenoic acid-to-arachidonic acid ratios. The changes in bacterial diversity contributed to 6-8% of the interindividual variance in change in colonic PGE2 (P = 0.001).ConclusionsDietary supplementation with ω-3 fatty acids had little effect on intestinal bacteria in healthy humans; however, an increase in diversity in the luminal brushings significantly predicted reductions in colonic PGE2. This trial was registered at www.clinicaltrials.gov as NCT01860352.

Dataset Information

?12-prostaglandin J3, an omega-3 fatty acid-derived metabolite, selectively ablates leukemia stem cells in mice.

Publications

Δ12-prostaglandin J3, an omega-3 fatty acid-derived metabolite, selectively ablates leukemia stem cells in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets