二十二碳六烯酸（DHA）处理通过细胞凋亡和细胞周期阻滞改变 MDA-MB-231 乳腺癌细胞和裸鼠来源肿瘤对阿霉素的反应。

Treatment with DHA Modifies the Response of MDA-MB-231 Breast Cancer Cells and Tumors from nu/nu Mice to Doxorubicin through Apoptosis and Cell Cycle Arrest.

机构信息

Department of Agricultural, Food & Nutritional Science, Faculty of Agricultural, Life & Environmental Sciences, University of Alberta, Edmonton, Alberta, Canada.

出版信息

J Nutr. 2019 Jan 1;149(1):46-56. doi: 10.1093/jn/nxy224.

DOI:10.1093/jn/nxy224

PMID:30601995

Abstract

BACKGROUND

Docosahexaenoic acid (DHA) has been shown to reduce growth of breast cancer cells in vitro and in vivo; it may also benefit the action of cytotoxic cancer drugs. The mechanisms for these observations are not completely understood.

OBJECTIVES

We sought to explore how pretreatment of MDA-MB-231 breast cancer cells with DHA alters gene expression with doxorubicin (DOX) treatment and confirm that feeding DHA to tumor-bearing nu/nu mice improves the efficacy of DOX.

METHODS

MDA-MB-231 cells were subjected to 4 conditions: a control mixture of 40 μM linoleic and 40 μM oleic acid (OALA), DHA (60 μM plus OALA), OALA DOX (0.41 μM), or DHA DOX (plus OALA) and assessed for effects on viability and function. Female nu/nu mice (6 wk old) bearing MDA-MB-231 tumors were randomly assigned to a nutritionally complete diet (20 g ± 2.8 g DHA/100 g diet) containing a polyunsaturated:saturated fat ratio of 0.5, with or without injections 2 times/wk of 5 mg DOX/kg for 4 wk.

RESULTS

Microarray and protein analysis indicated that DHA DOX cells, compared with OALA DOX, had upregulated expression of apoptosis genes, Caspase-10 (1.3-fold), Caspase-9 (1.4-fold), and Receptor (TNFRSF)-interacting serine-threonine kinase 1 (RIPK1) (1.2-fold), while downregulating cell cycle genes, Cyclin B1 (-2.1-fold), WEE1 (-1.6-fold), and cell division cycle 25 homolog C (CDC25C) (-1.8-fold) (P < 0.05). DHA DOX-treated mice had 50% smaller tumors than control mice (P < 0.05). Analysis of proapoptotic proteins from tumors of DHA DOX mice showed increased Caspase-10 (by 68%) and BH3 interacting domain death agonist (Bid) (by 50%), decreased B-cell CLL/lymphoma 2 (BCL2) (by 24%), and decreased cell cycle proteins Cyclin B1 and Cdc25c (both by 42%), compared with control mice (P < 0.05).

CONCLUSIONS

Supplementation with DHA facilitates the action of DOX in MDA-MB-231 cells and in nu/nu mice, which may occur via amplification of the effect of DOX on apoptosis and cell cycle genes.

摘要

背景

二十二碳六烯酸（DHA）已被证明可以减少乳腺癌细胞在体外和体内的生长；它还可能有益于细胞毒性抗癌药物的作用。这些观察结果的机制尚不完全清楚。

目的

我们试图探讨 MDA-MB-231 乳腺癌细胞用 DHA 预处理如何改变与阿霉素（DOX）治疗的基因表达，并证实给荷瘤 nu/nu 小鼠喂食 DHA 可提高 DOX 的疗效。

方法

将 MDA-MB-231 细胞置于 4 种条件下：对照混合物 40 μM 亚油酸和 40 μM 油酸（OALA）、DHA（60 μM 加 OALA）、OALA DOX（0.41 μM）或 DHA DOX（加 OALA），并评估对细胞活力和功能的影响。6 周龄雌性 nu/nu 小鼠（6 周龄）患有 MDA-MB-231 肿瘤，随机分为营养完整的饮食（20 g ± 2.8 g DHA/100 g 饮食），其中多不饱和：饱和脂肪比为 0.5，每周 2 次注射 5 mg DOX/kg，持续 4 周。

结果

微阵列和蛋白质分析表明，与 OALA DOX 相比，DHA DOX 细胞上调了凋亡基因的表达，包括 Caspase-10（1.3 倍）、Caspase-9（1.4 倍）和受体（TNFRSF）-相互作用丝氨酸-苏氨酸激酶 1（RIPK1）（1.2 倍），同时下调了细胞周期基因，细胞周期蛋白 B1（-2.1 倍）、WEE1（-1.6 倍）和细胞分裂周期 25 同源物 C（CDC25C）（-1.8 倍）（P < 0.05）。DHA DOX 治疗的小鼠的肿瘤比对照小鼠小 50%（P < 0.05）。DHA DOX 小鼠肿瘤中促凋亡蛋白的分析显示，Caspase-10（增加 68%）和 BH3 相互作用结构域死亡激动剂（Bid）（增加 50%）增加，B 细胞 CLL/淋巴瘤 2（BCL2）（减少 24%）和细胞周期蛋白 Cyclin B1 和 Cdc25c（均减少 42%）减少，与对照小鼠相比（P < 0.05）。