Sphingosine and its methylated derivative N,N-dimethylsphingosine (DMS) induce apoptosis in a variety of human cancer cell lines

Abstract

In the study of apoptosis initiated by various signals including ligands binding to cell membrane receptors such as Fas and TNFRI, the sphingomyelin pathway and its resulting metabolites, the sphingolipids, have been suggested to be involved in the signaling pathway. In earlier studies we presented data which indicated that sphingosine (Sph) itself was increased during apoptosis induced by phorbol myristate acetate (PMA) in HL60 cells and tumor necrosis factor (TNF) in neutrophils, and when added exogenously was able to induce apoptosis. We report here that Sph and its methylated derivative N,N,-dimethylsphingosine (DMS) are able to induce apoptosis in cancer cells of both hematopoietic and carcinoma origin. In human leukemic cell lines CMK-7, HL60 and U937, treatment with 20 microM Sph for 6 hr caused apoptosis in up to 90% of cells. Human colonic carcinoma cells HT29, HRT18, MKN74 and COLO205 were shown to be more susceptible to apoptosis upon addition of DMS (>50%) than of Sph (<50%), yet were weakly or not sensitive to N,N,N-trimethylsphingosine (TMS). Under the same conditions, in the presence of serum, neither Sph-1-phosphate nor ceramide analogues C2-, C6- or C8-ceramide were able to induce apoptosis in any cell lines. However, in the absence of serum, ceramide analogues induced apoptosis in leukemia cell lines after 18 hr, yet much less so than Sph or DMS. Furthermore, apoptosis induced by Sph or DMS could not be inhibited by the ceramide synthase inhibitor fumonisin B1. Apoptosis was not induced by sphingolipids in primary culture cells, such as HUVEC or rat mesangial cells, but was apparent in transformed rat mesangial cells. Additionally, apoptosis induced by Sph, DMS or C2Cer was inhibited by protease inhibitors. Our data further support the evidence that the catabolic pathway of sphingomyelin involving Sph and other metabolites is an integral part of the apoptosis pathway.

ChlamydiapneumoniaeInhibits Apoptosis in Human Peripheral Blood Mononuclear Cells Through Induction of IL-10

“…TNF-␣ also increases synthesis of NO in different cells, and this molecule has been extensively associated with induction of DNA damage and apoptosis (39 -42). Additionally, TNF-␣ may activate sphingomyelin breakdown into ceramide, which has a recognized role in apoptosis (43). IL-10, on the other hand, has been reported to have variable effects on apoptosis, depending upon the cell type and model systems used (44 -46).…”

Activation of caspase-3-like proteases in apoptosis induced by sphingosine and other long-chain bases in Hep3B hepatoma cells

“…For instance, sphingosine 1-phosphate stimulates cell proliferation of fibroblasts, whereas it induces growth arrest in breast cancer cells [39,40]. In addition, this sphingolipid can trigger apoptosis in HL60 and Hep3B cells [11,12]. Despite questions regarding their mechanisms of action, recent data indeed indicate that sphingolipids are potent anti-tumour agents.…”

“…Secondly, sphingolipids can effectively and specifically inhibit the chemotactic motility and invasiveness of tumour cells [42]. Thirdly, exogenously added sphingolipids exert low toxicity on normal fibroblasts or normal human umbilical-vein endothelial cells at concentrations that trigger apoptosis in different cancer cell lines [12]. Finally, and most importantly, sphingolipids can effectively inhibit the growth of cancer cells that are resistant to anti-cancer drugs, and which express high levels of P-glycoprotein, both in itro and in i o [43].…”

“…are highly bioactive compounds and are involved in diverse cell processes, including cell-cell interaction, cell proliferation, differentiation and apoptosis [9,10]. Previously, we and others have reported that several sphingolipids can regulate the expression of members of the bcl-2 gene family and trigger apoptosis in a variety of human cancer cell lines [11,12]. However, the downstream effectors activated by these sphingolipids in this apoptotic signalling pathway are still unknown.…”

Derivatives of monoglycerides as apoptotic agents in T-cells

“…Most notably, treatment of various cell types with ceramides or sphingosines have been shown to induce apoptosis. 14,15 Addition of either GD3 ganglioside, 16 or the alkyllysophospholipid edelfosine (1-O-octadecyl-2-Omethyl-rac-glycero-3-phosphocholine; ET-18-OCH3) 17,18 to leukemic cells has also been reported to trigger apoptosis. Moreover, tributyrin, a triglyceride analog of the short chain fatty acid butyrate, was demonstrated to induce cell death in MCF-7 human mammary carcinoma cells.…”