Docosahexaenoic acid enrichment of tumor phospholipid membranes increases tumor necroptosis in mice bearing triple negative breast cancer patient-derived xenografts

Marnie Newell; Susan Goruk; Julia Schueler; Vera Mazurak; Lynne-Marie Postovit; Catherine J Field

doi:10.1016/j.jnutbio.2022.109018

Docosahexaenoic acid enrichment of tumor phospholipid membranes increases tumor necroptosis in mice bearing triple negative breast cancer patient-derived xenografts

J Nutr Biochem. 2022 Sep:107:109018. doi: 10.1016/j.jnutbio.2022.109018. Epub 2022 Apr 27.

Authors

Marnie Newell¹, Susan Goruk¹, Julia Schueler², Vera Mazurak¹, Lynne-Marie Postovit³, Catherine J Field⁴

Affiliations

¹ Department of Agricultural, Food and Nutritional Science, Faculty of Agricultural, Life and Environmental Sciences, University of Alberta, Edmonton, Alberta, Canada.
² Charles River Discovery Research Services Germany, Freiburg, Germany.
³ Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
⁴ Department of Agricultural, Food and Nutritional Science, Faculty of Agricultural, Life and Environmental Sciences, University of Alberta, Edmonton, Alberta, Canada. Electronic address: catherine.field@ualberta.ca.

PMID: 35489658
DOI: 10.1016/j.jnutbio.2022.109018

Abstract

Docosahexaenoic acid (DHA) reduces breast cancer tumor growth in preclinical models. To better understand how DHA amplifies the actions of docetaxel (TXT) chemotherapy, we examined the effects of two doses of dietary DHA on tumor size, membrane DHA content and necroptosis using a drug resistant triple negative breast cancer (TNBC) patient derived xenograft (PDX) model. Female NOD.Cb-Prkdc^scidIl2rg mice bearing TNBC PDXs were randomized to one of three nutritionally complete diets (20% w/w fat): control (0% DHA), high DHA (3.8% HDHA), or low DHA (1.6% LDHA) with or without intraperitoneal injections of 5 mg/kg TXT, twice weekly for 6 weeks (n=8 per group). Tumors from mice fed either HDHA+TXT or LDHA+TXT were similar in size to each other, but were 36% and 32% smaller than tumors from mice fed control+TXT, respectively (P<.05). A dose effect of DHA incorporation was observed in plasma total phospholipids and in phosphatidylethanolamine and phosphatidylinositol. Both doses of DHA resulted in similarly increased necrotic tissue and decreased NFκB protein expression compared to control tumors, however only the HDHA+TXT had increased expression of necroptosis related proteins: RIPK1, RIPK3 and MLKL (P<.05). Increased MLKL was observed in the lipid raft portion of HDHA+TXT tumor extracts. This work confirms the efficacy of a combination therapy consisting of DHA supplementation and TXT chemotherapy using two doses of DHA as indicated by reduced tumor growth in a TNBC PDX model. Moreover, the results suggest that decreased growth may occur through increased DHA incorporation into tumor phospholipid membranes and necroptosis.

Keywords: breast cancer; docosahexaenoic acid; necroptosis; patient derived xenograft; tumor.

Publication types

Randomized Controlled Trial, Veterinary
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Disease Models, Animal
Docosahexaenoic Acids* / metabolism
Female
Heterografts
Mice
Mice, Inbred NOD
Necroptosis
Phospholipids / metabolism
Triple Negative Breast Neoplasms* / drug therapy
Triple Negative Breast Neoplasms* / pathology

Substances

Phospholipids
Docosahexaenoic Acids

Grants and funding

CIHR/Canada