Effect of Omega-3 Fatty Acids on Cancer Stem Cells

Summary

Principal Investigator: KUMBLE SANDEEP PRABHU
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2012-07-16 - 2016-04-30
more information: NIH RePORT

Top Publications

  1. pmc Evaluation of the stability, bioavailability, and hypersensitivity of the omega-3 derived anti-leukemic prostaglandin: Δ(12)-prostaglandin J3
    Avinash K Kudva
    Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania, United States of America
    PLoS ONE 8:e80622. 2013

Research Grants

Detail Information

Publications1

  1. pmc Evaluation of the stability, bioavailability, and hypersensitivity of the omega-3 derived anti-leukemic prostaglandin: Δ(12)-prostaglandin J3
    Avinash K Kudva
    Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, Pennsylvania, United States of America
    PLoS ONE 8:e80622. 2013
    ..In summary, our studies suggest Δ(12)-PGJ3 to be a promising bioactive metabolite for further evaluation as a potential drug candidate for treating CML. ..

Research Grants30

  1. Mechanistic Pharmacology of Anti-Mitotics and Apoptosis Regulation
    Timothy J Mitchison; Fiscal Year: 2013
    ..In aim 4 we will pursue several approaches towards translating mechanistic understanding from aims 1-3 into improved patient care. ..
  2. Structural bases of the functions of RNA-protein machines
    THOMAS ARTHUR STEITZ; Fiscal Year: 2013
    ..Also of interest will be the ways in which the structures and properties of RNA molecules can be utilized to carry out various biological functions often analogous to those performed by proteins. ..
  3. Chemopreventive effect of fish oil derived EPA in lung cancer
    Peiying Yang; Fiscal Year: 2013
    ..This proposal intends to define a novel targeted natural chemopreventive agent against lung cancer. ..
  4. Omega-3 Fatty Acids and Hepatic Carcinogenesis
    Tong Wu; Fiscal Year: 2013
    ..Results from the proposed studies will provide important mechanistic insight and therapeutic implications for utilizing omega-3 PUFAs for the chemoprevention and treatment of human hepatocellular carcinoma. ..
  5. PAPOVA VIRUS TRANSFORMING MECHANISMS
    DAVID MORSE LIVINGSTON; Fiscal Year: 2013
    ..The goal of this Program is to continue to shed new light on cellular transformation events that also underpin human cancer development and generate insights that lead to new cancer therapeutic strategies. ..
  6. Functional Analysis of Cyclooxygenase-2
    Lawrence J Marnett; Fiscal Year: 2013
    ..These substrate-selective inhibitors may represent candidate cancer chemopreventive agents that lack the gastrointestinal and cardiovascular side effects of currently marketed NSAIDs. ..
  7. Catalysis by Prostaglandin Endoperoxide H Synthases
    William L Smith; Fiscal Year: 2013
    ....
  8. A MULTILEVEL APPROACH TO ENERGY BALANCE AND CANCER ACROSS THE LIFECOURSE
    Graham A Colditz; Fiscal Year: 2013
    ..To address these aims, we propose four research projects and five cores that form a cohesive, transdisciplinary center focused on research, training/career development, and dissemination. ..