Doxorubicin effect is enhanced by sphingosine-1-phosphate signaling antagonist in breast cancer

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 (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. Results 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. 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.

Survival benefit of sphingosin‐1‐phosphate and receptors expressions in breast cancer patients

“…Some references providing clinical evidence to show the S1P axis involved in the therapies resistant of tumors. In Katsuta et al48 study, it suggested that the expression of sphingosine kinase 1 tended to be higher in doxorubicin‐resistant human cancer and cell lines. In Nagahashi et al49 recent study, they used FTY720 to target SPHK1/S1P/S1PR1 axis and suggested that this pathway is associated with obesity‐related inflammation and breast cancer metastasis.…”

Low DMT1 Expression Associates With Increased Oxidative Phosphorylation and Early Recurrence in Hepatocellular Carcinoma

“…To identify the features of the low DMT1-expressing HCC, which have worse DFS after liver resection, GSEA was conducted based on the 50 hallmark gene sets. 44 Intriguingly, oxidative phosphorylation and glycolysis gene sets were found to be enriched in DMT1 low tumors in addition to DNA repair and reactive oxygen species gene sets (Table 2). Respiratory metabolism-related gene sets, such as glycolysis (Normalized enrichment score [NES] ¼ À1.547, P ¼ 0.022), oxidative phosphorylation (NES ¼ À2.166, P < 0.001), which generates adenosine triphosphate (ATP) using pyruvate, a product of glycolysis, and reactive oxygen species pathway (NES ¼ À1.766, P ¼ 0.011), were enriched in the low DMT1expressing HCC among 50 hallmark gene sets ( Fig.…”

“…GSEA was performed comparing DMT1 high and low patients utilizing the Java GSEA implementation version 3.0 provided by the Broad Institute (http://software.broadinstitute.org/ gsea/index.jsp) as described previously. [42][43][44][45]…”

Targeting PP2A in cancer: Combination therapies

“…Combination of doxorubicin with FTY720 resulted in reduced inflammation and synergistic suppression of cancer growth in vitro and in vivo. Furthermore, in an obesity breast cancer model where mice were fed a high-fat diet, this combination therapy was also efficacious [82]. …”