FTY720 for cancer therapy (Review)

Abstract

Abstract. 2-Amino-2-[2-(4-octylphenyl)]-1,3-propanediol hydrochloride (FTY720) is a potent immunosuppressant which has been approved by the Food and Drug Administration (FDA) as a new treatment for multiple sclerosis. As an immunosuppressant, it displays its anti-multiple sclerosis, immunosuppressive effects by activating sphingosine-1-phosphate receptors (S1PRs). In addition to the immunosuppressive effects, FTY720 also shows preclinical antitumor efficacy in several cancer models. In most cases, phosphorylation of FTY720 is not required for its cytotoxic effect, indicating the involvement of S1PR-independent mechanisms which are starkly different from the immunosuppressive property of FTY720. In the present study, we reviewed the rapidly advancing field of FTY720 in cancer therapy as well as some molecular targets of the unphosphorylated form of FTY720.

Sphingosine-1-Phosphate Receptor-1 Promotes Environment-Mediated and Acquired Chemoresistance

“…FTY720 treatment is associated with adverse effects that include headache, influenza-like illness, fatigue, gastrointestinal dysfunction, hemorrhaging focal encephalitis as well as transient bradycardia, and skin cancer (55). On the other hand, in our human NB xenograft model we did not observe severe side-effects associated treatment with FTY720, which is consistent with several previous studies (48). …”

“…FTY720, which is phosphorylated by sphingosine kinase (SK)2 (44), interacts with S1PR1 at high affinity, leading to S1PR1 endocytosis and degradation in vitro (45) and in vivo (46,47). In addition to various types of cancer cells tested with FTY720 (48), it has also been demonstrated to inhibit NB tumor growth and enhance the anti-tumor effects of topotecan (49). Here we show that S1PR1 inhibition with FTY720 enhanced the anti-tumoral effects of etoposide in chemo-resistant tumors.…”

FTY720 induces autophagy-related apoptosis and necroptosis in human glioblastoma cells

“…Depending on distinct pathways for inducing apoptosis, apoptosis can be divided into two types, including the mitochondrial death pathway (intrinsic pathway of apoptosis) and the death receptor pathway (extrinsic pathway of apoptosis). The antitumor activity of FTY720 was reportedly attributed to different apoptotic pathways (Zhang et al, 2013a). In our study, the indicators of intrinsic pathway of apoptosis such as Bcl-xL, Bcl-2, Bax and cytochrome c remained unchanged in respond to FTY720.…”

Deregulation of the PP2A Inhibitor SET Shows Promising Therapeutic Implications and Determines Poor Clinical Outcome in Patients with Metastatic Colorectal Cancer

“…S6B). Interestingly, the observation that the PP2A activator FTY720, a drug with a promising preclinical antitumor efficacy in several cancer models including colorectal cancer (32,37) that acts blocking SET (31), is able to impair the resistance induced by SET (Fig. 3B) would suggest that those patients with SET overexpression could improve their outcomes with a future inclusion of an oxaliplatin-based treatment in combination with FTY720 in the clinical protocols.…”