Doxorubicin effect is enhanced by sphingosine-1-phosphate signaling antagonist in breast cancer.
J Surg Res
; 219: 202-213, 2017 11.
Article
en En
| MEDLINE
| ID: mdl-29078883
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 ANDMETHODS:
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.Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias de la Mama
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Doxorrubicina
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Clorhidrato de Fingolimod
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Inmunosupresores
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Neoplasias Mamarias Experimentales
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Antibióticos Antineoplásicos
Tipo de estudio:
Etiology_studies
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
Límite:
Animals
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Female
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Humans
Idioma:
En
Año:
2017
Tipo del documento:
Article