C6 ceramide dramatically enhances docetaxel-induced growth inhibition and apoptosis in cultured breast cancer cells: a mechanism study.
C6 ceramide dramatically enhances docetaxel-induced growth inhibition and apoptosis in cultured breast cancer cells: a mechanism study.
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DOI：
10.1016/j.yexcr.2014.12.017
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发表时间：
2015-03
影响因子：
3.7
通讯作者：
Lan Yang;Li-yun Zheng;Ye Tian;Zhi-qing Zhang;W. Dong;Xufen Wang;Xiao-Ying Zhang;C. Cao
中科院分区：
文献类型：
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作者：
Lan Yang;Li-yun Zheng;Ye Tian;Zhi-qing Zhang;W. Dong;Xufen Wang;Xiao-Ying Zhang;C. Cao
在这里，我们报道了多西紫杉醇和细胞渗透性短链神经酰胺（C6）的共同给药导致原代和转化乳腺细胞（MCF-7和MDA-231）的生长抑制和凋亡显着增加，这与线粒体通透性转换孔（mPTP）开放、显着的活性氧（ROS）产生和促凋亡相关。 AMP 蛋白激酶 (AMPK) 以及 c-Jun N 末端激酶 (JNK) 激活。相反，mPTP 阻断剂 sanglifehrin A (SfA) 或 ROS 清除剂 N-乙酰基-L-半胱氨酸 (NAC) 在很大程度上抑制共同给药引起的细胞毒性。此外，环孢素 A (CsA)、亲环蛋白-D（Cyp-D，关键的 mPTP 成分）抑制剂以及 Cyp-D RNA 沉默也通过联合治疗抑制了乳腺癌细胞死亡，而过度表达 Cyp-D 的细胞则表现出对多西他赛超敏反应。同时，JNK 和 AMPK 抑制减轻了培养的乳腺癌细胞中联合给药引起的细胞死亡。值得注意的是，C6 神经酰胺加多西紫杉醇在表达 HER-2 的 MDA-231 细胞中引起显着的人表皮生长因子受体 (HER)-1/-2 降解和下游 Akt/Erk 抑制。这些体外研究结果为进一步开发 C6 神经酰胺作为多西他赛的辅助治疗转移性乳腺癌提供了信心。
Here we reported that co-administration of docetaxel and a cell-permeable short-chain ceramide (C6) resulted in a striking increase in growth inhibition and apoptosis in primary and transformed breast cells (MCF-7 and MDA-231), which were associated with mitochondrial permeability transition pore (mPTP) opening, a significant reactive oxygen species (ROS) production and the pro-apoptotic AMP-Protein Kinase (AMPK) as well as c-Jun N-terminal kinases (JNK) activations. Contrarily, the mPTP blocker sanglifehrin A (SfA) or the ROS scavenger N-acetyl-l-cysteine (NAC) largely inhibited co-administration-induced cytotoxicity. Further, cyclosporin A (CsA), the inhibitor of cyclophilin-D (Cyp-D, the key mPTP component), as well as Cyp-D RNA silencing also suppressed breast cancer cell death by the co-treatment, while cells overexpressing Cyp-D showed hypersensitivity to docetaxel. Meanwhile, JNK and AMPK inhibition alleviated cell death induced by the co-administration in cultured breast cancer cells. Significantly, C6 ceramide plus docetaxel caused dramatic human epidermal growth factor receptor (HER)-1/-2 degradation and downstream Akt/Erk inhibition in HER-2 expressing MDA-231 cells. These in vitro findings provide confidence in support of further development of C6 ceramide as an adjunct of docetaxel for the treatment of the metastatic breast cancer.