title: Omega-3 fatty acids, EPA and DHA induce apoptosis and enhance drug sensitivity in multiple myeloma cells but not in normal peripheral mononuclear cells.
abstract: The n-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been shown to enhance the effect of chemotherapeutic drugs in clinical studies in cancer patients and to induce apoptotic tumor cell death in vitro. Until now, EPA and DHA have never been investigated in multiple myeloma (MM). Human myeloma cells (L363, OPM-1, OPM-2 and U266) and normal peripheral blood mononuclear cells were exposed to EPA and DHA, and effects on mitochondrial function and apoptosis, caspase-3 activation, gene expression and drug toxicity were measured. Exposure to EPA and DHA induced apoptosis and increased sensitivity to bortezomib in MM cells. Importantly, they did not affect viability of normal human peripheral mononuclear cells. Messenger RNA expression arrays showed that EPA and DHA modulated genes involved in multiple signaling pathways including nuclear factor (NF) κB, Notch, Hedgehog, oxidative stress and Wnt. EPA and DHA inhibited NFκB activity and induced apoptosis through mitochondrial perturbation and caspase-3 activation. Our study suggests that EPA and DHA induce selective cytotoxic effects in MM and increase sensitivity to bortezomib and calls for further exploration into a potential application of these n-3 polyunsaturated fatty acids in the therapy of MM.
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, the Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Abdi
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, the Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Garssen
authors.affiliation: Nutricia Advanced Medical Nutrition, Nutricia Research, Utrecht, the Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Faber
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, the Netherlands. Electronic address: f.a.m.redegeld@uu.nl.
authors.forename: F A
authors.initials: FA
authors.lastname: Redegeld
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D016718:Arachidonic Acid / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D016328:NF-kappa B; D011719:Pyrazines; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; D000069286:Bortezomib; D015118:Eicosapentaenoic Acid; C505407:CASP3 protein, human; D053148:Caspase 3
keywords: Apoptosis; DHA; EPA; Mitochondria; Multiple myeloma; NFκB; Oxidative stress