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Published on: December 26, 2016
Targeting Sphingolipids for Cancer Therapy
Osmel Companioni1, Cristina Mir1, Yoelsis Garcia-Mayea1
1Biomedical Research in Cancer Stem Cells Group, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
Abstract:
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.
Insights
Sphingolipid-targeting drugs show promise in cancer treatment, with fenretinide and α-galactosylceramide being most effective. Clinical trial outcomes vary, highlighting the need for further research into these cancer therapies.
Area of Science:
- Biochemistry
- Oncology
- Pharmacology
Background:
- Sphingolipids play crucial roles in cellular functions, including proliferation and cell death.
- Aberrant sphingolipid metabolism is implicated in cancer progression, proliferation, and metastasis.
- Several sphingolipid signaling modulators have been developed for potential cancer therapies.
Purpose of the Study:
- To review and analyze preclinical and clinical trial data of sphingolipid-targeting drugs for cancer treatment.
- To evaluate the efficacy and safety of these agents, alone or in combination with chemotherapy.
- To discuss the mechanisms of action and therapeutic potential of sphingolipid modulation in oncology.
Main Methods:
- Literature review of preclinical studies (in vitro and in vivo) and clinical trials.
- Analysis of drug efficacy, mechanisms of cell death (apoptosis, autophagy), and adverse effects.
- Comparison of outcomes for various sphingolipid-targeting agents including fenretinide, safingol, ABC294640, ceramide nanoliposomes (CNLs), SKI-II, α-galactosylceramide (α-GalCer), fingolimod, and sonepcizumab.
Main Results:
- Sphingolipid-targeting drugs demonstrated antitumor activity and synergism with chemotherapy in preclinical settings.
- Fenretinide and α-galactosylceramide showed the most significant efficacy.
- Clinical trial results were inconsistent; ABC294640 and safingol exhibited specific toxicities, while others lacked sufficient clinical data.
Conclusions:
- Sphingolipid modulation presents a viable strategy for cancer therapy, though clinical success varies among agents.
- Fenretinide and α-galactosylceramide are promising candidates for further clinical development.
- Further research is needed to overcome limitations and fully elucidate the therapeutic benefits of sphingolipid-targeting drugs in cancer treatment.
