The phosphorylated prodrug FTY720 is a histone deacetylase inhibitor that reactivates ERalpha expression and enhances hormonal therapy for breast cancer.

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Citation

Hait NC, Avni D, Yamada A, Nagahashi M, Aoyagi T, Aoki H, Dumur CI, Zelenko Z, Gallagher EJ, Leroith D, Milstien S, Takabe K, Spiegel S

The phosphorylated prodrug FTY720 is a histone deacetylase inhibitor that reactivates ERalpha expression and enhances hormonal therapy for breast cancer.

Oncogenesis. 2015 Jun 8;4:e156. doi: 10.1038/oncsis.2015.16.

PubMed ID
26053034 [ View in PubMed
]
Abstract

Estrogen receptor-alpha (ERalpha)-negative breast cancer is clinically aggressive and does not respond to conventional hormonal therapies. Strategies that lead to re-expression of ERalpha could sensitize ERalpha-negative breast cancers to selective ER modulators. FTY720 (fingolimod, Gilenya), a sphingosine analog, is the Food and Drug Administration (FDA)-approved prodrug for treatment of multiple sclerosis that also has anticancer actions that are not yet well understood. We found that FTY720 is phosphorylated in breast cancer cells by nuclear sphingosine kinase 2 and accumulates there. Nuclear FTY720-P is a potent inhibitor of class I histone deacetylases (HDACs) that enhances histone acetylations and regulates expression of a restricted set of genes independently of its known effects on canonical signaling through sphingosine-1-phosphate receptors. High-fat diet (HFD) and obesity, which is now endemic, increase breast cancer risk and have been associated with worse prognosis. HFD accelerated the onset of tumors with more advanced lesions and increased triple-negative spontaneous breast tumors and HDAC activity in MMTV-PyMT transgenic mice. Oral administration of clinically relevant doses of FTY720 suppressed development, progression and aggressiveness of spontaneous breast tumors in these mice, reduced HDAC activity and strikingly reversed HFD-induced loss of estrogen and progesterone receptors in advanced carcinoma. In ERalpha-negative human and murine breast cancer cells, FTY720 reactivated expression of silenced ERalpha and sensitized them to tamoxifen. Moreover, treatment with FTY720 also re-expressed ERalpha and increased therapeutic sensitivity of ERalpha-negative syngeneic breast tumors to tamoxifen in vivo more potently than a known HDAC inhibitor. Our work suggests that a multipronged attack with FTY720 is a novel combination approach for effective treatment of both conventional hormonal therapy-resistant breast cancer and triple-negative breast cancer.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
FingolimodHistone deacetylase 1ProteinHumans
Unknown
Inhibitor
Details