Eicosapentaenoic acid (EPA) is an omega (?)-3 polyunsaturated fatty acid (PUFA) whose consumption has increased over time. Apart from cardiovascular benefits, EPA is reported to have chemo preventive effects in form of induction of apoptosis of many cancer cell lines, but the mechanisms are unclear. We have identified cyclooxygenase (COX)-2-derived metabolites of EPA-derived prostaglandin D3 (PGD3) in immune cells (macrophages and T-cells) in the form of ?12-PGJ3 (most predominant and stable metabolite), and 15-deoxy-?12-14-PGJ3 (15d-PGJ3), collectively referred to as cyclopentenone PGs (CyPGs). Based on our recently published and preliminary data, we believe that CyPGs target cancer stem cells for apoptosis at nM concentrations. To illustrate this novel and previously undescribed anticancer property, we have utilized a well-established model of chronic myelogenous leukemia (CML) that involves leukemia stem cells (LSCs). LSCs reside at the apex of a developmental hierarchy and facilitate the continued expansion of bulk tumor cells leading to relapse of the disease. Our studies are based on the hypothesis that CyPGs derived from EPA selectively target LSCs via the activation of CyPG-receptor-p53 signaling axis for apoptosis. The anti-leukemic role of bioactive components derived from EPA will be tested in the CML model, where primary murine hematopoietic stem cells (HSCs) transduced to express the human fusion protein, BCR-Abl, will be transplanted into mice fed a high EPA diet to mimic human consumption. Given that this is a first study of its kind, we will examine the metabolism of dietary EPA to ?12-PGJ3 and 15-deoxy- ?12,14-PGJ3 in-vivo to confirm endogenous production of CyPGs in sufficient amounts (nM range) in Aim 1.
In Aim 2, we will test the effects of EPA-derived endogenous PGJ3 on the ablation of LSCs and address the role of COX inhibitors (commonly used NSAIDs) in the blunting of the effects of EPA.
In Aim 3, we will elucidate pathways of activation of p53 via the binding of ?12- PGJ3 to CyPG (DP) receptors expressed in LSCs. Our long-term goal is to understand the health benefits of bioactive metabolites of ?-3 fatty acids and translate these findings in CML patients.
The application is based on a relatively understudied area of complementary and alternative medicine of omega-3 fatty acid, eicosapentaenoic acid (EPA), and its role in the targeting of cancer stem cells for apoptosis. Using a model of chronic myelogenous leukemia (CML), we hypothesize that some of the novel metabolites of EPA, in form of cyclopentenone prostaglandin J3 series, initiate apoptosis of leukemia stem cells that lead to CML.
|Nicolaou, K C; Heretsch, Philipp; ElMarrouni, Abdelatif et al. (2014) Total synthesis of ?¹²-prostaglandin J?, a highly potent and selective antileukemic agent. Angew Chem Int Ed Engl 53:10443-7|