Katsuta Eriko, Yan Li, Nagahashi Masayuki, Raza Ali, Sturgill Jamie L, Lyon Debra E, Rashid Omar M, Hait Nitai C, Takabe Kazuaki
Breast Surgery, Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York; Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia; Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York.
Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, New York.
J Surg Res. 2017 Nov;219:202-213. doi: 10.1016/j.jss.2017.05.101. Epub 2017 Jun 29.
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, Gene Expression Omnibus data sets, and National Cancer Institute-60 panel were used for gene expressions and gene set enrichment analysis. 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, 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, sphingosine kinase 1, S1P receptor 1, interleukin 6, and STAT3 were overexpressed 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 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.
多柔比星是乳腺癌最常用的化疗药物之一；然而，其应用受到耐药性和副作用的限制。我们推测，在多柔比星中添加鞘氨醇-1-磷酸（S1P）受体功能拮抗剂FTY720，可通过抑制药物诱导的炎症来增强其疗效。
使用癌症基因组图谱、基因表达综合数据库和美国国立癌症研究所60细胞株进行基因表达和基因集富集分析。采用E0771同基因乳腺肿瘤细胞。将喂食西方高脂饮食的OB/OB小鼠用作肥胖模型。
多柔比星治疗后，人乳腺癌中信号转导与转录激活因子3（STAT3）表达显著增加，这表明多柔比星可引发炎症。在对多柔比星耐药的人类癌症和细胞系中，产生S1P并将炎症与癌症联系起来的鞘氨醇激酶1的表达往往更高。在小鼠乳腺癌模型中，多柔比星治疗组中鞘氨醇激酶1、S1P受体1、白细胞介素6和STAT3均过表达，而添加FTY720后所有这些均被显著抑制。联合治疗在体外和体内均协同抑制肿瘤生长。此外，联合治疗在肥胖乳腺癌模型中显示出更高的疗效，在该模型中，高体重指数显示出无病生存期和总生存期较差的趋势，且人类患者和志愿者的血清S1P水平较高。
我们发现FTY720通过抑制药物诱导的炎症增强了多柔比星的疗效，联合治疗在肥胖相关乳腺癌中显示出更强的效果。
