Targeting Sphingolipids for Cancer Therapy

Abstract

Cancer; Sphingolipids; Therapy

Cáncer; Esfingolípidos; Terapia

Càncer; Esfingolípids; Teràpia

Sphingolipids are an extensive class of lipids with different functions in the cell, ranging from proliferation to cell death. Sphingolipids are modified in multiple cancers and are responsible for tumor proliferation, progression, and metastasis. Several inhibitors or activators of sphingolipid signaling, such as fenretinide, safingol, ABC294640, ceramide nanoliposomes (CNLs), SKI-II, α-galactosylceramide, fingolimod, and sonepcizumab, have been described. The objective of this review was to analyze the results from preclinical and clinical trials of these drugs for the treatment of cancer. Sphingolipid-targeting drugs have been tested alone or in combination with chemotherapy, exhibiting antitumor activity alone and in synergism with chemotherapy in vitro and in vivo. As a consequence of treatments, the most frequent mechanism of cell death is apoptosis, followed by autophagy. Aslthough all these drugs have produced good results in preclinical studies of multiple cancers, the outcomes of clinical trials have not been similar. The most effective drugs are fenretinide and α-galactosylceramide (α-GalCer). In contrast, minor adverse effects restricted to a few subjects and hepatic toxicity have been observed in clinical trials of ABC294640 and safingol, respectively. In the case of CNLs, SKI-II, fingolimod and sonepcizumab there are some limitations and absence of enough clinical studies to demonstrate a benefit. The effectiveness or lack of a major therapeutic effect of sphingolipid modulation by some drugs as a cancer therapy and other aspects related to their mechanism of action are discussed in this review.

This work was supported by grants from the Instituto de Salud Carlos III (ISCIII; PI20/00556 and CP03/00101 [ML]) and CIBERONC (ML). This work was also co-financed by the European Regional Fund (ERDF) and AECC (Spanish Association of Cancer Research) (Founding Ref. GC16173720CARR [ML]). YG-M and CM were supported by the VHIR and iP-FIS (ISCIII) fellowships, respectively.