Doxorubicin effect is enhanced by sphingosine-1-phosphate signaling antagonist in breast cancer.
Doxorubicin effect is enhanced by sphingosine-1-phosphate signaling antagonist in breast cancer.
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DOI：
10.1016/j.jss.2017.05.101
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发表时间：
2017-11
期刊：
影响因子：
--
通讯作者：
Takabe K
中科院分区：
文献类型：
--
作者：
Katsuta E;Yan L;Nagahashi M;Raza A;Sturgill JL;Lyon DE;Rashid OM;Hait NC;Takabe K
阿霉素是乳腺癌最常用的化疗药物之一；然而，它的使用受到耐药性和副作用的限制。我们假设在阿霉素中加入鞘氨醇-1-磷酸（S1P）受体功能拮抗剂FTY720可以通过抑制药物性炎症来增强其作用。使用癌症基因组图谱（TCGA）、GEO数据集和NCI-60面板进行基因表达和基因集富集分析（GSEA）。采用E0771同基因乳腺肿瘤细胞。以饲喂西式高脂饲料的OB/OB小鼠为肥胖模型。在人乳腺癌中，阿霉素治疗后STAT3的表达显著增加，提示阿霉素引起炎症。SphK1是一种产生S1P并连接炎症和癌症的酶，在阿霉素耐药的人类癌症和细胞系中，SphK1的表达往往更高。在小鼠乳腺癌模型中，SphK1、S1P受体1 （S1PR1）、IL6和STAT3在阿霉素治疗组中过表达，而FTY720的加入则显著抑制了这些表达。联合治疗协同抑制肿瘤生长在体外和体内。此外，联合治疗在肥胖乳腺癌模型中显示出更高的疗效，在肥胖乳腺癌模型中，高体重指数（BMI）显示出更差的无病生存和总体生存的趋势，并且在人类患者和志愿者中血清S1P水平较高。我们发现FTY720通过抑制药物性炎症来增强阿霉素的疗效，并且联合治疗对肥胖相关性乳腺癌的效果更强。
Doxorubicin is one of the most commonly used chemotherapeutic drugs for breast cancer; however, its use is limited by drug resistance and side-effects. We hypothesized that adding FTY720, a sphingosine-1- phosphate (S1P) receptor functional antagonist, to doxorubicin would potentiate its effects by suppression of drug-induced inflammation. The Cancer Genome Atlas (TCGA), GEO datasets, and NCI-60 panel were used for gene expressions and gene set enrichment analysis (GSEA). E0771 syngeneic mammary tumor cells were used. OB/OB mice fed with western high fat diet were used as an obesity model. STAT3 expression was significantly increased after doxorubicin treatment in human breast cancer that implicates that doxorubicin evokes inflammation. Expression of sphingosine kinase 1 (SphK1), the enzyme that produces S1P and links inflammation and cancer, tended to be higher in doxorubicin resistant human cancer and cell lines. In a murine breast cancer model, SphK1, S1P receptor 1 (S1PR1), IL6 and STAT3 were over-expressed in the doxorubicin treated group, whereas all of them were significantly suppressed with addition of FTY720. Combination therapy synergistically suppressed cancer growth both in vitro and in vivo. Furthermore, combination therapy showed higher efficacy in an obesity breast cancer model, where high body mass index (BMI) demonstrated trends toward worse disease free and overall survival, and high serum S1P levels in human patients and volunteers. We found that FTY720 enhanced the efficacy of doxorubicin by suppression of drug-induced inflammation, and combination therapy showed stronger effect in obesity-related breast cancer.
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影响因子：
--
作者：
Alshaker H;Wang Q;Kawano Y;Arafat T;Böhler T;Winkler M;Cooper C;Pchejetski D
通讯作者：
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影响因子：
4.8
作者：
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影响因子：
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作者：
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影响因子：
4.8
作者：
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通讯作者：
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