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.

中文翻译：

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在体外乳腺癌细胞的全细胞或脂筏磷脂和体内肿瘤磷脂中，二十二碳六烯酸的掺入不受阿霉素化疗的影响。

为了更好地了解二十二碳六烯酸 (DHA) 如何改善阿霉素 (DOX) 的作用，我们检查了 DHA ± DOX 对 MDA-MB-231 和 MCF-7 乳腺癌细胞的全细胞和脂筏磷脂 (PL) 变化的影响。我们试图确认 MDA-MB-231 细胞的 PL DHA 含量的相对变化是否可以扩展到来自在喂食补充 DHA 饮食±DOX 的小鼠中生长的 MDA-MB-231 肿瘤的 PL。DHA 处理并未改变 PL 组成，但 DOX 使 MCF-7 细胞脂筏中的磷脂酰丝氨酸比例增加了两倍（p < 0.001）。不管 DOX，MDA-MB-231 细胞中 DHA 的相对掺入百分比高于 MCF-7 细胞中磷脂酰丝氨酸、磷脂酰乙醇胺和磷脂酰胆碱（全细胞和脂筏）；和更高的磷脂酰乙醇胺与磷脂酰胆碱相比（MCF-7 细胞的 4.4 倍和 MDA-MB-231 细胞的 6 倍）。DHA 处理增加了 MDA-MB-231 细胞中的二十碳五烯酸和二十二碳五烯酸，但不增加 MCF-7 细胞。在所有 PL 部分（鞘磷脂除外）中，MDA-MB-231 细胞、MCF-7 细胞和 MDA-MB-231 肿瘤中 DHA 含量的增加与花生四烯酸的减少相对应（p < 0.05）。给小鼠喂食 2.8% (w/w 脂肪) DHA ± DOX 增加肿瘤坏死区域 ( p< 0.05)。该研究确定了 DHA 在人乳腺癌细胞系之间的差异整合到全细胞和脂筏中。然而，在每个细胞系中，这种掺入并未被 DOX 改变，证实 DOX 不会改变膜脂组成。此外，我们的研究结果表明，体外观察到的膜变化可转化为体内变化，并且 DHA + DOX 可以通过增加坏死来促进抗癌作用。