HMG-CoA Reductase Inhibitor Simvastatin Inhibits Cell Cycle Progression at the G1/S Checkpoint in Immortalized Lymphocytes from Alzheimer’s Disease Patients Independently of Cholesterol-Lowering Effects

Abstract

Recent work has suggested that statins may exert beneficial effects on patients suffering from Alzheimer's disease (AD). The pharmacological effects of statins extend beyond their cholesterol-lowering properties. Based on the antineoplastic and apoptotic effects of statins in several cell types, we hypothesized that statins may be able to protect neurons by controlling the regulation of cell cycle. A growing body of evidence indicates that neurodegeneration involves the activation of cell cycle machinery in postmitotic neurons. We and others have presented direct evidence to support the hypothesis that the failure of cell cycle control is not restricted to neurons in AD patients, but that it occurs in peripheral cells as well. For these reasons, we found it worthy to study the role of simvastatin on cell proliferation in immortalized lymphocytes from AD patients. We report here that simvastatin (SIM) inhibits the serum-mediated enhancement of cell proliferation in AD by blocking the events critical for G 1 /S transition. SIM induces a partial blockade of retinoblastoma protein phosphorylation and inhibition of cyclin E/cyclin-dependent kinase (CDK)2 activity associated with increased levels of the CDK inhibitors p21Cip1 and p27 kip1 . These effects of SIM on AD lymphoblasts are dependent on inhibition of the proteasome-mediated degradation of p21 and p27 proteins. The antiproliferative effect of this natural statin may provide a therapeutic approach for AD disease.

Simvastatin overcomes the resistance to serum withdrawal-induced apoptosis of lymphocytes from Alzheimer’s disease patients

“…In contrast with the effect of SIM increasing the levels of CDK inhibitors, p21 and p27 in AD lymphoblasts under proliferative conditions [32], SIM drastically decreased the p21 content of serum-deprived lymphoblasts from AD. Cell death induced by SIM showed characteristics of apoptosis, since it was prevented by a pan-caspase inhibitor, and showed dependence on caspase-3 and 7 activation.…”

“…In this regard, it is worth mentioning that SIM addition to AD cells was able to restore the ''normal'' cell response to serum stimulation [32] or withdrawal (this manuscript), by blunting the enhanced proliferative activity of AD cells or sensitizing cells to apoptosis in the absence of serum. In both situations, SIM was able to increase [32] or decrease the levels of p21 of AD lymphoblasts to reach those of control cells. It remains to be demonstrated whether SIM would protect neurons in AD brain from apoptosis by modulating p21 content.…”

“…Moreover, we have recently reported that SIM, a lipophilic statin, inhibits cell-cycle progression at the G1-S checkpoint in immortalized lymphocytes from AD patients [32]. These cell lines were also found to be more resistant to serum withdrawal [33].…”

SCA8 repeat expansion: large CTA/CTG repeat alleles in neurological disorders and functional implications

“…These observations coincide with the length-dependent toxicity of DMPK CUG repeats on Caenorhabditis elegans (Chen et al 2007). Although lymphoblastoid cells we used are not of neuronal origin, immortalized lymphoblast cells from patients with Alzheimer's disease are frequently used to mirror changes thought to occur in the brain Sala et al 2008). Thus, our results suggest that the SCA8 88-95 repeats are toxic to human cells.…”

Differential and Joint Effects of Metformin and Statins on Overall Survival of Elderly Patients with Pancreatic Adenocarcinoma: A Large Population-Based Study

“…The main effect of statins is to inhibit cholesterol synthesis through inhibition of the rate-limiting enzyme HMG-CoA reductase (44). In addition, statins have cancer chemotherapeutic properties through various mechanisms: halting cell cycle progression and proliferation (45); increasing radiosensitization in cancer cells (46); promoting apoptosis (47, 48); and impairing metastasis of tumors (49). Based on our current understanding of the diverse molecular pathways of statin action, a protective effect of statins on overall survival of pancreatic cancer patients is biologically plausible.…”