Clinical application of ceramide in cancer treatment

Abstract

Development of innovative strategies for cancer treatment is a pressing public health issue. Despite recent advances, the mechanisms of cancer progression and the resistance to cancer treatment have not been fully elucidated. Sphingolipids, including ceramide and sphingoshin-1-phosphate, are bioactive mediator that regulates cancer cell death and survival through the dynamic balance of what has been termed the 'sphingolipid rheostat'. Specifically, ceramide, which acts as the central hub of sphingolipid metabolism, is generated via three major pathways by many stressors, including anti-cancer treatments, environmental stresses, and cytokines. We have previously shown in breast cancer patients that elevated ceramide correlated with less aggressive cancer phenotypes, leading to a prognostic impact. Recent studies showed that ceramide have the possibility of becoming the reinforcing agent of cancer treatment as well as other roles such as nanoparticles and diagnostic biomarker. We review ceramide as one of the key molecules to investigate in overcoming resistance to current drug therapies and in becoming one of the newest cancer treatments.

Lipid composition of the cancer cell membrane

“…Therefore, the increased ceramide biosynthesis appears to be harmless, or even has therapeutic potential (Woodcock 2006). Some novel strategies of cancer therapies aim to overexpress the ceramide biosynthetic pathway enzymes and eventually lead to programmed cancer cell death (Moro et al, 2019). Enzymes utilised in cancer treatment include serine C-palmitoyl transferase (CPT) -sensitising breast cancer cells to chemotherapy (Wang et al, 2002), ceramide synthase 1 (CERS1) -inducing mitophagy and acute myeloid leukaemia (AML) cell death (Dany et al, 2016), ceramide synthase 6 (CERS6) -modulating caspase activation in head and neck cancer (White-Gilbertson et al, 2009), dihydroceramide desaturase (DES)leading to cell cycle arrest in neuroblastoma cells (Kraveka et al, 2007), acidic sphingomyelinase (ASMase) -inducing lymphoblasts apoptosis (Santana et al, 1996) and neutral sphingomyelinase (NSMase)utilised in breast cancer therapy (Hwang et al, 2015).…”

The role of lipid species in membranes and cancer-related changes

“…They claim that the "simple notion of the balance" between Sph-1-phosphate and Cer as dictating cell survival is not in accordance with several recent studies, e.g., that selective Sph kinase 1 inhibitors do not affect cancer cell proliferation or survival, and the fact that several studies demonstrate higher Cer levels in some metastatic cancers. Moro et al [128] discuss different aspects of Cer related to cancer, including using Cer as an anti-cancer agent, regulating Cer metabolism to suppress cancer, and using Cer as a biomarker.…”

Cholesterol and Sphingolipid Enriched Lipid Rafts as Therapeutic Targets in Cancer

“…Many studies have suggested that the SphK1/S1P axis could play a role in the promotion of several types of tumors, based on the overexpression of SphK1 in tumor cell lines and in patient samples, and sometimes, on the measured increased S1P levels in tumors and/or in patient blood. These studies have recently been reviewed for breast [ 46 ], ovarian, [ 47 ], and gastrointestinal cancers [ 48 ], hepatocellular carcinoma [ 49 ], melanoma [ 50 ] and glioblastoma [ 51 ]. High S1P in breast tumor tissue is significantly associated with lymphnode metastasis [ 52 ].…”