Ceramide is a sphingolipid metabolite that induces malignancy cell death. CLL
Ceramide is a sphingolipid metabolite that induces malignancy cell death. CLL cells with nanoliposomal C6-ceramide could potentially be an effective therapy for leukemia by targeting the Warburg effect. Introduction Sphingolipids are a class of complex cellular lipids that serve both a structural role in the cellular membrane as well as an intracellular signaling role within the cell. Several types of sphingolipid metabolites have been shown to influence the balance between mitogenesis and apoptosis. Of particular interest is usually the sphingolipid metabolite, ceramide, which is usually known to regulate differentiation, senescence and cell cycle arrest. Induction of cell death by this endogenous lipid-derived second messenger occurs either via apoptotic, autophagic, or necrotic cell death pathways [1,2,3]. Ceramide inhibits cell proliferation and induces apoptosis via mechanisms such as dephosphorylation and/or inactivation of molecules including Akt, phospholipase Deb, ERK, Bcl-2, survivin, PKC-, and pRB [4,5,6], as well as activation of JNK kinases[4,7], or PKC zeta which, results in suppression of Akt-dependent mitogenesis . Therefore, it is usually not amazing that dysregulated ceramide metabolism and signaling has been linked to a variety of human diseases, including malignancy. Based on its ability to selectively block tumor initiation and metastasis, ceramide has been termed the tumor-suppressor lipid . Many malignancy chemotherapies have been shown to generate endogenous ceramide, and when generation of ceramide is usually inhibited, the cellular response to cytotoxic chemotherapeutic brokers decreases . In addition, it has previously been shown that accumulation of endogenous ceramides or exogenous ceramide treatment is usually more harmful to tumor cells than to normal cells [6,9]. However, the exact mechanism of selectivity is usually unknown. One proposed mechanism for how ceramide mediates cell death induction is usually through downregulation of nutrient transporter proteins possibly via nutrient deprivation .. As malignancy cells have an increased dependence on glucose, these nutrient transporters and/or the glycolytic pathway are typically upregulated. One hallmark of malignancy cells is usually their ability to avidly take up glucose and convert it to lactate, even in the presence of sufficient oxygen. Deemed the Warburg effect, this altered glycolytic dependency favors less efficient generation of ATP compared to the oxidative phosphorylation process which occurs in normal cells [11,12]. Many human cancers display increased levels of glycolytic enzymes compared to normal tissue . Acvrl1 Consequently, a variety of chemotherapeutic glycolytic inhibitors or PET modalities are currently under investigation as potential Warburg-targeted therapeutic or diagnostic imaging tools [14,15]. Recently, the role of sphingosine kinases in regulating the Warburg effect in prostate malignancy cells has been documented in the books . Treatment of LNCaP prostate malignancy cells with SKi, a non-selective sphingosine kinase inhibitor, significantly increases intracellular levels of ceramide and sphingosine and indirectly antagonizes the Warburg effect, producing in apoptosis of LNCaP cells. Chronic lymphocytic leukemia (CLL) is usually the most common B-cell malignancy in the Western world which presently Exatecan mesylate has no Exatecan mesylate known curative therapy . Previous studies have exhibited that treatment with exogenous short-chain C2-ceramide results in induction of cell death in malignant cells isolated from CLL patients . Recent improvements in nanotechnology have illustrated the feasibility of generating nanoliposomes that encapsulate hydrophobic compounds, like ceramide, to facilitate treatment of CLL. While it is usually comprehended how nanoliposomal ceramide induces cell death in Exatecan mesylate several types of cancers and hematological malignancies, the effect of nanoliposomal ceramide treatment in CLL remains ambiguous. Currently, several nanoliposomal formulations of anti-cancer drugs have been approved by the FDA and are the standard of care . For instance, the efficacy of fludarabine, the malignancy chemotherapy generally used to treat CLL patients, and which functions via intracellular ceramide accumulation, is usually enhanced after being encapsulated in nanoliposomes [20,21]. Our laboratory has exhibited that encapsulation of ceramide in a nanoliposome versus non-liposomal organic formulations results in an increase in cytotoxic potential with significant less toxicity . Our laboratory has also exhibited that the short chain C6-ceramide nanoliposomal.