Docosahexaenoic Acid Incorporation Is Not Affected by Doxorubicin Chemotherapy in either Whole Cell or Lipid Raft Phospholipids of Breast Cancer Cells in vitro and Tumor Phospholipids in vivo.

Abstract

To better understand how docosahexaenoic acid (DHA) improves the effects of doxorubicin (DOX), we examined DHA ± DOX on changes in whole cell and lipid raft phospholipids (PL) of MDA-MB-231 and MCF-7 breast cancer cells. We sought to confirm whether the relative changes in PL DHA content of MDA-MB-231 cells could be extended to PL from MDA-MB-231 tumors grown in mice fed a DHA supplemented diet ±DOX. Treatment with DHA did not change PL composition yet DOX increased the proportion of phosphatidylserine in MCF-7 cell lipid rafts by two-fold (p < 0.001). Regardless of DOX, the relative percent incorporation of DHA was higher in MDA-MB-231 cells compared to MCF-7 cells in phosphatidylserine, phosphatidylethanolamine, and phosphatidylcholine (whole cell and lipid rafts); and higher in phosphatidylethanolamine vs. phosphatidylcholine (4.4-fold in MCF-7 and 6-fold in MDA-MB-231 cells respectively). DHA treatment increased eicosapentaenoic acid and docosapentaenoic acid in MDA-MB-231 cells but not MCF-7 cells. Increased DHA content in MDA-MB-231 cells, MCF-7 cells, and MDA-MB-231 tumors in all PL moieties (except sphingomyelin) corresponded with reduced arachidonic acid (p < 0.05). Feeding mice 2.8% (w/w of fat) DHA ± DOX increased tumor necrotic regions (p < 0.05). This study established differential incorporation of DHA into whole cell and lipid rafts between human breast cancer cell lines. However, within each cell line, this incorporation was not altered by DOX confirming that DOX does not change membrane lipid composition. Furthermore, our findings indicate that membrane changes observed in vitro are translatable to in vivo changes and that DHA + DOX could contribute to the anticancer effects through increased necrosis.