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Published on: June 9, 2023
Doxorubicin effect is enhanced by sphingosine-1-phosphate signaling antagonist in breast cancer
Eriko Katsuta1, Li Yan2, Masayuki Nagahashi3
1Breast 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.
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.
Insights
Adding FTY720 to doxorubicin chemotherapy enhances breast cancer treatment by reducing inflammation. This combination therapy is particularly effective in obesity-related breast cancer, improving outcomes.
Area of Science:
- Oncology
- Pharmacology
- Immunology
Background:
- Doxorubicin is a key breast cancer chemotherapy drug, but drug resistance and side effects limit its use.
- Inflammation plays a role in doxorubicin resistance and cancer progression.
- FTY720, a sphingosine-1-phosphate (S1P) receptor antagonist, is investigated for its potential to mitigate these issues.
Purpose of the Study:
- To evaluate if FTY720 can potentiate doxorubicin's efficacy in breast cancer treatment.
- To investigate the mechanism of FTY720 in suppressing doxorubicin-induced inflammation.
- To assess the combination therapy's effectiveness, especially in obesity-related breast cancer models.
Main Methods:
- Analysis of gene expression data from The Cancer Genome Atlas, Gene Expression Omnibus, and NCI-60 panel.
- Utilized E0771 syngeneic mammary tumor cells and an obesity mouse model (OB/OB mice on a high-fat diet).
- Assessed STAT3, sphingosine kinase 1, S1P receptor 1, and interleukin 6 expression and their modulation by doxorubicin and FTY720.
Main Results:
- Doxorubicin treatment increased STAT3 expression, indicating induced inflammation.
- Sphingosine kinase 1 expression was higher in doxorubicin-resistant cancers.
- Combination therapy with FTY720 significantly suppressed inflammatory markers (sphingosine kinase 1, S1P receptor 1, IL-6, STAT3) and synergistically inhibited cancer growth in vitro and in vivo.
- The combination therapy demonstrated enhanced efficacy in an obesity-related breast cancer model.
Conclusions:
- FTY720 enhances doxorubicin efficacy by suppressing drug-induced inflammation.
- Combination therapy is more effective in obesity-related breast cancer.
- This approach holds promise for improving treatment outcomes, particularly in patients with obesity and breast cancer.
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