Abstract
Statins, the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are widely used cholesterol-lowering drugs. Convincing evidence indicates that statins stimulate apoptotic cell death in several types of proliferating tumor cells in a cholesterol-lowering-independent manner. The objective here was to elucidate the molecular mechanism by which statins induce lymphoma cells death. Statins (atorvastatin, fluvastatin and simvastatin) treatment enhanced the DNA fragmentation and the activation of proapoptotic members such as caspase-3, PARP and Bax, but suppressed the activation of anti-apoptotic molecule Bcl-2 in lymphoma cells including A20 and EL4 cells, which was accompanied by inhibition of cell survival. Both increase in levels of reactive oxygen species (ROS) and activation of p38 MAPK and decrease in mitochondrial membrane potential and activation of Akt and Erk pathways were observed in statin-treated lymphoma cells. Statin-induced cytotoxic effects, DNA fragmentation and changes of activation of caspase-3, Akt, Erk and p38 were blocked by antioxidant (N-acetylcysteine) and metabolic products of the HMG-CoA reductase reaction, such as mevalonate, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). These results suggests that HMG-CoA reductase inhibitors induce lymphoma cells apoptosis by increasing intracellular ROS generation and p38 activation and suppressing activation of Akt and Erk pathways, through inhibition of metabolic products of the HMG-CoA reductase reaction including mevalonate, FPP and GGPP.
Highlights
Inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase are used to treat hypercholesterolemia
Cells were incubated with atorvastatin, fluvastatin or simvastatin at concentrations ranging from 0–5 mM for 24 and/or 48 h, respectively
Both cell viability inhibition and DNA fragmentation induced by fluvastatin were remarkably suppressed by Mev, farnesyl pyrophosphate (FPP) or geranylgeranyl pyrophosphate (GGPP) (Figures 8b and c). These data indicate that mevalonate pathway may contribute to fluvastatin-induced apoptosis in lymphoma cells. Convincing evidence from both in vitro and mouse model data suggest that statins can be used as a potential cancer therapeutic depending on the type of cancer cell, but the Previous studies have reported that statins can induce cell death in various cancer cells in a cell type-dependent manner.[11,13,15,17,26]
Summary
Inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase (statins) are used to treat hypercholesterolemia Convincing evidence from both in vitro and in vivo data has demonstrated that statins exert pleiotropic actions beyond their lipid-lowering effects, including immune regulation[8] and cancer prevention.[9,10] Statins have been demonstrated to induce cell cycle arrest and cell death in various cancer cells such as multiple myeloma cells,[11] pancreatic cancer cells,[12] non-small lung cancer cells,[13] waldenstrom macroglobulinemia cells,[14] glioblastoma cell lines[15] and HT29 cells.[16] A recent study has shown that simvastatin inhibits proliferation of MCF-7 cells in parallel with an increase in reactive oxygen species (ROS) production.[17]. A high-dose of atorvastatin induces oxidative DNA damage in human peripheral blood lymphocytes.[19]
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