FTY720 (Fingolimod) sensitizes hepatocellular carcinoma cells to sorafenib‐mediated cytotoxicity

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. The multityrosine kinase inhibitor sorafenib is used in the therapy of advanced disease. However, the effects of sorafenib are limited, and combination treatments aiming at improved survival are encouraged. The sphingosine analog FTY720 (Fingolimod), which is approved for treatment of multiple sclerosis, has shown tumor suppressive effects in cell lines and animal models of HCC. In the present study, we combined sorafenib with FTY720 in order to sensitize the HCC cell lines Huh7 and HepG2 to sorafenib treatment. Using the XTT assay we show that noncytotoxic doses of FTY720 synergistically enhanced the decrease in viability caused by treatment of both cell lines with increasing doses of sorafenib. Further studies in Huh7 revealed that combined treatment with FTY720 and sorafenib resulted in G1 arrest and enhanced cell death measured using flow cytometry analysis of cells labeled with propidium iodide (PI)/Annexin-V and PI and 4′,6-diamidino-2-phenylindole-staining of nuclei. In addition, signs of both caspase-dependent and – independent apoptosis were observed, as cotreatment with FTY720 and sorafenib caused cytochrome c release and poly-ADP ribose polymerase-cleavage as well as translocation of Apoptosis-inducing factor into the cytosol. We also detected features of autophagy blockage, as the protein levels of LC3-II and p62 were affected by combined treatment with FTY720 and sorafenib. Together, our results suggest that FTY720 sensitizes HCC cells to cytotoxic effects induced by treatment with sorafenib alone. These findings warrant further investigations of combined treatment with sorafenib and FTY720 in vivo in order to develop more effective treatment of HCC.

RETRACTED: Melatonin prevents deregulation of the sphingosine kinase/sphingosine 1‐phosphate signaling pathway in a mouse model of diethylnitrosamine‐induced hepatocellular carcinoma

“…Anti‐S1P monoclonal antibodies that specifically neutralize and target S1P are effective against breast, lung, or ovarian cancer cells, melanoma cells, and renal cancer models in vivo, while SphK inhibition has been shown to reduce the viability of glioblastoma multiforme cells, neuroblastoma cells, several types of leukemia cells, and various solid tumor cell lines . The selective SphK1 inhibitor FTY720, which has cytotoxic effects in various cancers, induces apoptosis in cell lines and animal models of HCC and sensitizes HCC cells to sorafenib‐mediated cytotoxicity . Another SphK inhibitor, N,N ‐dimethylsphingosine (DMS) is known to suppress proliferation and migration of HCC cells .…”

Targeted co-delivery of Beclin 1 siRNA and FTY720 to hepatocellular carcinoma by calcium phosphate nanoparticles for enhanced anticancer efficacy

“…10 Recently, FTY720 was found to inhibit the growth of various tumors, including HCC tumors. 40,41 Because of its nontoxicity, specific cytotoxicity toward tumors and high oral bioavailability, FTY720 has great potential for tumor therapy. However, after exploring the use of FTY720 in various cancers, studies have shown that this drug substantially induces autophagy in tumor cells, which protects them from damage and reduces apoptosis.…”

Fingolimod sensitizes EGFR wild‑type non‑small cell lung cancer cells to lapatinib or sorafenib and induces cell cycle arrest

“…In most cases, the anticancer mechanism of FTY720 involves inhibition of the proto-oncogene sphingosine kinase 1; however, the anticancer properties of FTY720 may be attributable to its effects on several other molecular targets (24,25). Furthermore, FTY720 was reported to modulate autophagy; a number of studies have reported the induction of autophagy by FTY720 (26)(27)(28)(29), while others have reported autophagy suppression (30)(31)(32)(33). Autophagy exhibits complex, context-dependent properties in cancer, and interventions that stimulate or inhibit autophagy have been proposed as potential anti-cancer therapies (34).…”