Ceramide--antiestrogen nanoliposomal combinations--novel impact of hormonal therapy in hormone-insensitive breast cancer.
Ceramide--antiestrogen nanoliposomal combinations--novel impact of hormonal therapy in hormone-insensitive breast cancer.
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DOI：
10.1158/1535-7163.mct-12-0594
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发表时间：
2012-11
影响因子：
5.7
通讯作者：
Cabot MC
中科院分区：
文献类型：
--
作者：
Morad SA;Levin JC;Shanmugavelandy SS;Kester M;Fabrias G;Bedia C;Cabot MC
尽管鞘脂神经酰胺显示出有效的肿瘤抑制作用，但由于其溶解度、摄取、生物利用度和代谢转化较差，对其利用的努力受到阻碍。因此，确定提高疗效的途径对于开发基于神经酰胺的疗法是必要的。在这项研究中，我们使用了突变型p53、三阴性乳腺癌（TNBC）细胞（一种高度难以治疗的乳腺癌）和细胞渗透性纳米脂质体c6 -神经酰胺，以及抗雌激素的他莫昔芬（tamoxifen），后者已被证明是神经酰胺代谢的有效调节剂。我们首次表明，纳米脂质体他莫昔芬增强了培养TNBC细胞中纳米脂质体c6 -神经酰胺的细胞毒性，这种反应伴随着分别在18和2小时诱导细胞周期阻滞在G1和G2， caspase依赖性诱导DNA片段，以及增强线粒体和溶酶体膜通透性。他莫昔芬代谢物也有效。只有他莫昔芬能促进溶酶体膜的通透性。此外，我们首次证明，他莫昔芬抑制酸性神经酰胺酶，在完整细胞测定；这种影响是不可逆转的。总之，我们的研究结果表明，他莫昔芬通过联合靶向细胞周期穿越、溶酶体和线粒体完整性，放大了c6 -神经酰胺的抗增殖作用。我们认为，c6 -神经酰胺诱导的细胞凋亡被他莫昔芬对溶酶体的影响和可能伴随的酸性神经酰胺酶的抑制放大，这可能导致鞘氨醇1-磷酸水平下降。这种药物方案可以作为化疗耐药和三阴性乳腺癌的一种有希望的治疗方法，因此代表了他莫昔芬的适应症，无论雌激素受体状态如何。
Although the sphingolipid ceramide exhibits potent tumor suppressor effects, efforts to harness this have been hampered by poor solubility, uptake, bioavailability, and metabolic conversion. Therefore, identification of avenues to improve efficacy is necessary for development of ceramide-based therapies. In this study we used mutant p53, triple negative breast cancer (TNBC) cells, a type of breast cancer highly refractory to treatment, and cell-permeable nanoliposomal C6-ceramide in conjunction with the antiestrogen tamoxifen, which has been shown to be an effective modulator of ceramide metabolism. We show for the first time that nanoliposomal tamoxifen enhances nanoliposomal C6-ceramide cytotoxicity in cultured TNBC cells, a response that was accompanied by induction of cell cycle arrest at G1 and G2, caspase-dependent induction of DNA fragmentation, and enhanced mitochondrial and lysosomal membrane permeability, at 18 and 2 hr, respectively. Tamoxifen metabolites were also effective. Only tamoxifen promoted lysosomal membrane permeability. In addition, we demonstrate for the first time that tamoxifen inhibits acid ceramidase, as measured in intact cell assays; this effect was irreversible. Together, our findings show that tamoxifen magnifies the antiproliferative effects of C6-ceramide via combined targeting of cell cycle traverse and lysosomal and mitochondrial integrity. We adduce that C6-ceramide-induced apoptosis is amplified by tamoxifen's impact on lysosomes and perhaps accompanying inhibition of acid ceramidase, which could result in decreased levels of sphingosine 1-phosphate. This drug regimen could serve as a promising therapy for chemoresistant and triple negative types of breast cancer, and thus represents an indication for tamoxifen, irrespective of estrogen receptor status.