Δ12-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 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.

Deleting Mcl-1 in mast cells: getting 2 birds with 1 stone

“…These findings are entirely consistent with the properties of PolyP presented by Choi et al, and with their observation that activated platelets and platelet releasates support factor XI activation in a manner that is blocked by a PolyP specific binding protein. 1 Taken as a whole, this work…”

“…In this issue of Blood, Choi and colleagues present intriguing results showing that a nonprotein, inorganic polyphosphate (PolyP), can enhance thrombin generation by serving as a cofactor for formation of factor XIa. 1 F actor XI, the precursor of factor XIa, differs structurally in several important respects from the vitamin K-dependent (VKD) coagulation protease zymogens (the thrombin precursor prothrombin and factors VII, IX, and X). 2 For example, factor XI lacks the Gladomain through which the VKD proteins bind to phospholipid membranes.…”

“…1 Previously, PolyP has been shown to influence blood coagulation by (1) induction of factor XII activation (contact activation), (2) acceleration of factor V activation by factor Xa, and (3) enhancing fibrin fibril thickness. 1,6,7 PolyP is a linear polymer of inorganic phosphate groups linked by high-energy phosphoanhydride bonds. A minimum PolyP chain length is required to support factor XI activation by thrombin, suggesting a template mechanism in which factor XI and thrombin bind to the polymer in proximity to each other.…”

“…1 M cl-1 belongs to the bcl-2 family proteins and has been considered a master regulator of cell survival. Earlier studies that used Mcl-1-floxed mice that express Cre recombinase under different cell type-specific promoters demonstrated that Mcl-1 plays an essential role in maintaining survival of multiple cell types including lymphocytes, neutrophils, hepatocytes, and neurons.…”

The antileukemic activity of Δ12-PGJ3

“…4 Hegde et al show that n-3 PUFA metabolites, endogenously produced by macrophages treated with eicosapentaenoic acid, have activity against leukemia stem cells at nanomolar concentrations. 1 Leukemia stem cells are notoriously refractory to conventional drugs; consequently, their eradication is an important unrealized therapeutic goal. The current study offers hope for the establishment of a new class of drugs with antileukemic activity.…”