Sphingolipid-based drugs selectively kill cancer cells by down-regulating nutrient transporter proteins

Abstract

Cancer cells are hypersensitive to nutrient limitation because oncogenes constitutively drive glycolytic and tricarboxylic acid (TCA) cycle intermediates into biosynthetic pathways. Because the anaplerotic reactions that replace these intermediates are fueled by imported nutrients, the cancer cell’s ability to generate ATP becomes compromised under nutrient-limiting conditions. In addition, most cancer cells have defects in autophagy, the catabolic process that provides nutrients from internal sources when external nutrients are unavailable. Normal cells, in contrast, can adapt to nutrient stress that kills cancer cells by becoming quiescent and catabolic. We show that FTY720, a water soluble sphingolipid drug that is effective in many animal cancer models, selectively starves cancer cells to death by down-regulating nutrient transporter proteins. Consistent with a bioenergetic mechanism of action, FTY720 induced homeostatic autophagy. Cells were protected from FTY720 by cell permeable nutrients or by reducing nutrient demand, but blocking apoptosis was ineffective. Importantly, AAL-149, an FTY720 analog that lacks FTY720’s dose limiting toxicity, also triggered transporter loss and killed patient-derived leukemias while sparing cells isolated from normal donors. Because they target the metabolic profile of cancer cells rather than specific oncogenic mutations, FTY720 analogs like AAL-149 should be effective against many different tumor types, particularly in combination with drugs that inhibit autophagy.

Sphingolipids: regulators of crosstalk between apoptosis and autophagy

“…In contrast, dimethylsphingosine, SKI-2, and ABC294640 induced autophagic cell death that was associated with a decrease in Akt activity and upregulation of Beclin 1 ( 85,143 ), mechanisms similar to that described by ceramide. Furthermore, the water-soluble sphingosine analog FTY720 has been shown to induce caspase-independent cell death through the downregulation of nutrient transporters and induction of autophagy ( 144,145 ). However, treatment with FTY720, which is reported to inhibit S1P lysase ( 146 ), SK1 ( 147 ), and CerS ( 148,149 ), induced such effects independent of ceramide production and S1P receptors ( 145 ), suggesting a mechanism that is distinct from ceramide and the SK inhibitors described above.…”

Sphingosine-1-phosphate and estrogen signaling in breast cancer

“…First, FTY720 has anti-proliferative actions in many types of cancer cells without affecting normal cells (Romero Rosales et al, 2011). Moreover, FTY720 is a substrate and thus a competitive inhibitor of SphK1 and SphK2, decreasing levels of prosurvival S1P and increasing levels of pro-apoptotic sphingosine (Pyne et al, 2014).…”

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

“…It is noted that the therapeutic FTY720 doses (of 5–10 mg/kg) that we and others have used in animal cancer models (50,51) are higher (by fold 10) than that used in models of cerebral ischemia (52,53) or multiple sclerosis (54). 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).…”