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 AE 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 AEDOX. Treatment with DHA did not change PL composition yet DOX increased the proportion of phosphatidylserine in MCF-7 cell lipid rafts by twofold (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 AE DOX increased tumor necrotic regions

Anthracyclins increase free PUFAs and etherPEs with PUFAs as potential hallmarks of lipid peroxidation and ferroptosis

“…In contrast, Achkar et al in 2020 found a general downregulation of most metabolites and lipids (including etherPEs with PUFAs) in egg-developed tumors (MDA-MB-231) treated with DOX 31 . This finding is in apparent contradiction to our results and those reported by Newel et al in 2020 30 . Nevertheless, the study of Achkar et al in 2020 about DOX-treated solid tumors contained alive, damaged, and dead cell debris 31 .…”

“…We did not observe a general change of lipids in HepG2 and Huh7, except for the increase of PUFAs, etherPEs with PUFAs, and PGs (Figure 3). This observation agrees with the recent study by Newell et al in 2020, which does not report strong changes in the lipid families in breast cancer cells (MDA-MB-231 and MCF-7) treated with DOX in combination with fatty acids 30 . They did not include etherPEs nor PGs in their study, so, as new result, we observed that both anthracyclins upregulated these families of glycerophospholipids in HepG2 and Huh7 (PUFAs and etherPEs with PUFAs increased in SNU449 as well, Figure 3).…”

“…Among different PUFAs, FA(22:6) presents the highest enhancement of cytotoxicity 48 . This effect has also been demonstrated in animal models 30 . However, the mechanism(s) of how PUFAs enhance anthracyclin-induced cell death is(are) not fully understood.…”

“…It is known that PUFAs potentiate the effect of DOX in vitro and in animal models 30,67 . This effect might be general, as it would potentiate the lipid peroxidation in ferroptosis induced by anthracyclins.…”

Anthracyclins Increase PUFAs: Potential Implications in ER Stress and Cell Death

“…It is known that PUFAs potentiate the effect of DOX in vitro and in animal models [ 69 , 70 ]. This effect might be general, as it would potentiate the lipid peroxidation in ferroptosis induced by anthracyclins.…”