Eriko Katsuta1, Li Yan2, Masayuki Nagahashi3, Ali Raza4, Jamie L Sturgill5, Debra E Lyon6, Omar M Rashid7, Nitai C Hait8, Kazuaki Takabe9. 1. 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. 2. Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, New York. 3. Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. 4. Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia. 5. Biobehavioral Laboratory Services, Department of Family and Community Health Nursing, Virginia Commonwealth University, Richmond, Virginia. 6. Department of Biobehavioral Nursing Science, College of Nursing, University of Florida, Gainesville, Florida. 7. Holy Cross Hospital Michael and Dianne Bienes Comprehensive Cancer Center, Fort Lauderdale, Florida; Massachusetts General Hospital, Boston, Massachusetts; University of Miami Miller School of Medicine, Miami, Florida; Nova Southeastern University School of Medicine, Fort Lauderdale, Florida. 8. Breast Surgery, Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York; Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York. 9. 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 Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, the State University of New York, Buffalo, New York. Electronic address: kazuaki.takabe@roswellpark.org.
Abstract
BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: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. MATERIALS AND METHODS: 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/OBmice fed with western high-fat diet were used as an obesity model. RESULTS:STAT3 expression was significantly increased after doxorubicin treatment in humanbreast 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 humancancer and cell lines. In a murinebreast 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 humanpatients and volunteers. CONCLUSIONS: 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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