ABSTRACT
Oxysterols are 27-carbon oxidation products of cholesterol metabolism. Oxysterols possess several biological actions, including the promotion of cell death. Here, we examined the ability of several oxysterols to induce short-term death in cancerous (human breast cancer and mouse skin melanoma cells) and non-cancerous (human endothelial cells and lung fibroblasts) cell lines. We determined cell viability, Ki67 expression, cell cycle regulation, and apoptosis after 24-h incubations with oxysterols. We found that different oxysterols had different effects on the studied parameters. Moreover, the effects depended on cell type and oxysterol concentration. Three cytotoxic oxysterols (7-ketocholesterol, cholestane-3ß-5α-6ß-triol, and 5α-cholestane-3ß,6ß-diol) inhibited the S phase and stimulated the G0/G1 or G2/M phases. These oxysterols promoted apoptosis, determined with Annexin V and propidium iodide assays. These results showed that different oxysterols have cytotoxic effects depending on the cell line. The findings suggest a potential pharmacological utility of cytotoxic oxysterols.
Subject(s)
Apoptosis/drug effects , Oxysterols/pharmacology , Cell Cycle/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Dose-Response Relationship, Drug , Humans , Structure-Activity RelationshipABSTRACT
Oxysterols are oxidized products of cholesterol that play several roles in various pathophysiological processes, including the control of lipid metabolism, immunological processes, and cytotoxicity. Mesenchymal stem cells are multipotent cells with properties of self-renewal and the ability to differentiate into other cell types, including osteoblasts and adipocytes. Here, we review the literature regarding the effects of oxysterols on mesenchymal stem cell differentiation and the main signaling pathways involved in this process.
Subject(s)
Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/drug effects , Oxysterols/pharmacology , Animals , Cell Differentiation/drug effects , Humans , Oxysterols/chemistry , Oxysterols/metabolismABSTRACT
ATP-binding cassette (ABC) transporters constitute a ubiquitous superfamily of membrane proteins responsible for the translocation of several substances across membranes using the chemical energy provided by ATP hydrolysis. ABC transporters participate in many physiological and pathophysiological processes, including cholesterol and lipid transportation and multidrug resistance. Oxysterols are the products of cholesterol oxidation, formed by both enzymatic and non-enzymatic mechanisms. The role of oxysterols in cholesterol metabolism and several diseases has been widely investigated, but many questions remain to be answered. Several lines of evidence link ABC transporter functions with cholesterol and oxysterol metabolism. This review discusses ABC transporters, oxysterols, and how they interact with each other.
Subject(s)
ATP-Binding Cassette Transporters/metabolism , Sterols/metabolism , Animals , Cell Membrane/metabolism , Cholesterol/metabolism , Humans , Liver X Receptors , Orphan Nuclear Receptors/metabolism , Oxidation-Reduction , Receptors, Steroid/metabolism , Sterol Regulatory Element Binding Proteins/metabolismABSTRACT
Azidothymidine (AZT) is an antiretroviral drug that affects cell proliferation, apoptosis, and the NF-κB pathway. As multiple myeloma (MM) presents with constitutive activation of NF-κB, we analyzed the effect of AZT on human MM cell lines. We evaluated the cytotoxic effect of AZT in human MM cell lines sensitive (8226/S) or resistant to doxorubicin (8226/DX5) and human T cell lymphoblast-like cells, uterine sarcoma cells, and HUVEC using MTT assay. Cytotoxicity was also evaluated in vivo in nude mice xenografted with 8226/S tumor. The effect of AZT on the expression of genes involved in cell proliferation, apoptosis, angiogenesis, and the NF-κB pathway was analyzed in the xenografts using real-time polymerase chain reaction. AZT was effective against both 8226/S and 8226/DX5 cells in a dose and time-dependent manner (p = 0.02) in vitro and promoted cell cycle arrest in S phase in these cells. The tumor volume was lower in mice treated with AZT compared to untreated mice (p = 0.0003). AZT down-regulated the pro-proliferative genes encoding AKT1, MYC, STAT1, MAPK8, MAPK9, CCL-3, Bcl-3, and cyclin D2; pro-angiogenenic genes encoding VEGF and IL8; and genes involved in cell adhesion (ICAM1 and FN1) and the NF-κB pathway. AZT up-regulated the expression of tumor suppressor gene FOXP1 and the pro-apoptotic genes encoding BID, Bcl-10, and caspase-8. Thus, we demonstrated the cytotoxic effect of AZT in human MM cell lines for the first time. Our data may provide the rationale for future clinical trials of AZT for treating MM.
