Targeting Sphingolipids for Cancer Therapy

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.

Investigating the Potential Use of Chemical Biopsy Devices to Characterize Brain Tumor Lipidomes

“…Moreover, since the membrane’s fluidity and ability to adapt to dynamic changes is associated with changes in lipid composition, changes in membrane composition may be an indicator of ongoing carcinogenesis [ 47 ]. It has previously been reported that, apart from changes in the phospholipid content, neoplasms also exhibit alterations in their sphingolipid content [ 42 , 48 ]. In our study, the HGG samples showed significantly decreased levels of SM 42:1;O2; however, the biochemical analysis of this observation may be vague due to the detection of only one sphingolipid showing statistically significant change ( Table S5 ).…”

Multifunctional Role of Lipids in Modulating the Tumorigenic Properties of 4T1 Breast Cancer Cells

“…There are contradicting reports in the literature on the effect of SM on cancer cells. Both pro-tumor and anti-tumor properties have been reported in different types of cancer [39,42,78]. A study by Yan et al, demonstrated that in a triple-negative breast cancer mouse model, SM inhibited the proliferation and metastasis of cancer cells by reversing the polarization of M2 macrophages in tumors [79].…”

“…In contrast, a more recent study identified SMs as key secreted factors that possess natural cancer-suppressing mechanisms [38]. In vivo, Cer is converted to SM by the addition of a phosphorylcholine headgroup by SM synthase [39], while sphingomyelinase can reduce the levels of SM by conversion of SM to ceramide (Cer) [40,41]. Tumor progression has been linked to a disturbed metabolic balance of SM and Cer [42].…”

Targeting Nutrient Dependency in Cancer Treatment

“…Indeed, preclinical use of acid sphingomyelinase which cleaves the sphingolipid or sphingomyelin into ceramide has been demonstrated in cancer therapy (126). In addition, molecules such as fenretinide, safingol, ABC294640, ceramide nanoliposomes (CNLs), SKI-II, a-galactosylceramide, fingolimod and sonepcizumab that modulating sphingolipid signaling have been exploited to induce cancer cell death through apoptosis or autophagy dependent manners (127). However, it remains unclear to what extent cancer cells exhibit dependency on extracellular sphingolipids, since sphingolipids imported from fetal calf serum in vitro are entirely catabolized by cultured cells and the role of sphingolipid-transporting proteins as cancer therapeutic targets remains elusive (128,129).…”