A Dansyl-Modified Sphingosine Kinase Inhibitor DPF-543 Enhanced De Novo Ceramide Generation

Abstract

Sphingosine-1-phosphate (S1P) synthesized by sphingosine kinase (SPHK) is a signaling molecule, involved in cell proliferation, growth, differentiation, and survival. Indeed, a sharp increase of S1P is linked to a pathological outcome with inflammation, cancer metastasis, or angiogenesis, etc. In this regard, SPHK/S1P axis regulation has been a specific issue in the anticancer strategy to turn accumulated sphingosine (SPN) into cytotoxic ceramides (Cers). For these purposes, there have been numerous chemicals synthesized for SPHK inhibition. In this study, we investigated the comparative efficiency of dansylated PF-543 (DPF-543) on the Cers synthesis along with PF-543. DPF-543 deserved attention in strong cytotoxicity, due to the cytotoxic Cers accumulation by ceramide synthase (CerSs). DPF-543 exhibited dual actions on Cers synthesis by enhancing serine palmitoyltransferase (SPT) activity, and by inhibiting SPHKs, which eventually induced an unusual environment with a high amount of 3-ketosphinganine and sphinganine (SPA). SPA in turn was consumed to synthesize Cers via de novo pathway. Interestingly, PF-543 increased only the SPN level, but not for SPA. In addition, DPF-543 mildly activates acid sphingomyelinase (aSMase), which contributes a partial increase in Cers. Collectively, a dansyl-modified DPF-543 relatively enhanced Cers accumulation via de novo pathway which was not observed in PF-543. Our results demonstrated that the structural modification on SPHK inhibitors is still an attractive anticancer strategy by regulating sphingolipid metabolism.

Targeting sphingosine kinase 1 in p53KO thymic lymphoma

“…These differences could be explained by the very short half‐life of PF543 and the fact that SK1 is not inhibited during all the interval following each treatment. Molecular modifications have been applied to PF543 to improve its anticancer potential 63 or to extend its inhibitory capacity to additional sphingolipid enzymes 64 ; however, these new compounds were used at higher concentrations than the original drug, which could reduce specificity. The short half‐life of PF543 in mice raises the need to identify either new inhibitors or additional molecular modifications to increase PF543 stability in biological systems and improve its bioavailability in mouse models of tumor growth.…”

The Role of Sphingolipids Metabolism in Cancer Drug Resistance

“…This is the case of the SPHK1 inhibitor PF-543 since it has been demonstrated that its dansylated form (DPF-543) provides high cytotoxicity. This compound also triggers aSMase activation, leading to a higher accumulation of ceramides within the cell ( 119 ). Other SPHK inhibitors, such as F-12509, SKI-I and FTY720 (Fingolimod), specifically inhibit SPHK1; ABC294640 (Opaganib) and K145 specifically inhibit SPHK2; and SKI-II which inhibits both SPHK1 and SPHK2.…”