Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

Abstract

Sphingolipids are major constituents of the cells with emerging roles in the regulation of cellular processes. Deregulation of sphingolipid metabolism is reflected as various pathophysiological conditions including metabolic disorders and several forms of cancer. Ceramides, ceramide-1-phosphate (C1P), glucosyl ceramide (GluCer), sphingosine and sphingosine-1-phosphate (S1P) are among the bioactive sphingolipid species that have important roles in the regulation of cell death, survival and chemotherapeutic resistance. Some of those species are known to accumulate in the cells upon chemotherapy while some others are known to exhibit an opposite pattern. Even though the length of fatty acid chain has a deterministic effect, in general, upregulation of ceramides and sphingosine is known to induce apoptosis. However, S1P, C1P and GluCer are proliferative for cells and they are involved in the development of chemoresistance. Therefore, sphingolipid metabolism appears as a good target for the development of novel therapeutics or supportive interventions to increase the effectiveness of the chemotherapeutic drugs currently in hand. Some approaches involve manipulation of the synthesis pathways yielding the increased production of apoptotic sphingolipids while the proliferative ones are suppressed. Some others are trying to take advantage of cytotoxic sphingolipids like short chain ceramide analogs by directly delivering them to the malignant cells as a distinct chemotherapeutic intervention. Numerous studies in the literature show the feasibility of those approaches especially in acute and chronic leukemias. This review compiles the current knowledge about sphingolipids and their roles in chemotherapeutic response with the particular attention to leukemias.

Chemically Induced Brain Cancer in Sprague-Dawley Rats: Changed Lipidomics Mimics the Human Conditions

“…TMZ also causes DNA double-strand breaks and has been shown to promote the accumulation of ceramide in GBM cells [38]. This is consistent with the known effects of many chemotherapies, which often activate ceramide formation through multiple mechanisms, including the activation of ceramide synthases, with this ceramide accumulation playing a major role in the mechanism of action of many of these agents [39][40][41]. Thus, the current therapies for GBM work in part by altering sphingolipid metabolism to enhance pro-apoptotic ceramide levels.…”

“…Thus, the current therapies for GBM work in part by altering sphingolipid metabolism to enhance pro-apoptotic ceramide levels. Heightened ceramide metabolism via, for example, the enhanced levels of sphingosine kinases, acid ceramidase or glucosylceramide synthase, commonly observed in many cancers, may clear this elevated ceramide and overcome radio/chemotherapy [39,40].…”

Targeting the Sphingolipid System as a Therapeutic Direction for Glioblastoma

“…TMZ also causes DNA double-strand breaks and has been shown to promote the accumulation of ceramide in GBM cells [125]. This is consistent with the known effects of many chemotherapies, which often activate ceramide formation through multiple mechanisms, including the activation of ceramide synthases, with this ceramide accumulation playing a major role in the mechanism of action of many of these agents [90,[129][130][131][132][133][134][135]. Thus, the current therapies for GBM work in part by altering sphingolipid metabolism to enhance pro-apoptotic ceramide levels.…”

“…Thus, the current therapies for GBM work in part by altering sphingolipid metabolism to enhance pro-apoptotic ceramide levels. Heightened ceramide metabolism via, for example, the enhanced levels of sphingosine kinases, acid ceramidase or glucosylceramide synthase, commonly observed in many cancers, may clear this elevated ceramide and overcome radio/chemotherapy-induced cell death, providing a mechanism for cancer resistance to these therapies [129][130][131]136]. Notably, analysis of the expression levels of sphingolipid metabolic enzymes in GBM show small but significant differences compared to the normal brain (Figure 3).…”

Triangulated Mal-Signaling in Alzheimer's Disease: Roles of Neurotoxic Ceramides, ER Stress, and Insulin Resistance Reviewed

“…Appreciation of the large number of variations in ceramide structure and subcellular localization has led to the recogniztion that ceramide signaling effects might be cataloged according to their molecular structures. Thus far, emphasis has been placed on fatty acid chain length and glycosylation or phosphorylation of the sphingolipid [109–111]. Earlier studies demonstrated that complex sphingolipids including gangliosides [112], and long-chain naturally occurring ceramides, i.e., up to 24 carbon atoms in length [113] function by stimulating positive cellular responses such as growth, while sphingosine-containing lipids, including shorter-chain ceramides, have inhibitory effects that result in increased apoptosis, cytotoxicity, or impaired growth [112, 114, 115].…”