Clinical Studies Of Statins Research Articles

Effect of Statin Lipophilicity on the Proliferation of Hepatocellular Carcinoma Cells

The HMG-CoA reductase inhibitors, statins, are drugs used globally for lowering the level of cholesterol in the blood. Different clinical studies of statins in cancer patients have indicated a decrease in cancer mortality, particularly in patients using lipophilic statins compared to those on hydrophilic statins. In this paper, we selected two structurally different statins (simvastatin and pravastatin) with different lipophilicities and investigated their effects on the proliferation and apoptosis of hepatocellular carcinoma cells. Lipophilic simvastatin highly influences cancer cell growth and survival in a time- and concentration-dependent manner, while pravastatin, due to its hydrophilic structure and limited cellular uptake, showed minimal cytotoxic effects.

Very low LDL-C levels may safely provide additional clinical cardiovascular benefit: the evidence to date.

SummaryBackgroundCardiovascular disease (CVD) is the leading cause of death in Europe and increased low‐density lipoprotein cholesterol (LDL‐C) is a major contributor to CVD risk. Extensive evidence from clinical studies of statins has demonstrated a linear relationship between LDL‐C levels and CVD risk. It has been proposed that lower LDL‐C levels than those currently recommended may provide additional clinical benefit to patients.AimThis review summarises the genetic and clinical evidence on the efficacy and safety of achieving very low LDL‐C levels.MethodsRelevant epidemiological and clinical studies were identified using PubMed and by searching abstracts published at major congresses.ResultsGenetic evidence demonstrates that individuals with naturally very low LDL‐C levels are healthy and have a low risk of CVD. Clinical evidence has shown that those patients who achieve very low LDL‐C levels through using lipid‐lowering therapies (LLTs), such as statins, have reduced CVD risk compared with patients who only just achieve recommended target LDL‐C levels. These data show that the incidence of adverse events in patients achieving very low LDL‐C levels using LLT is comparable to those reaching the recommended LDL‐C targets.ConclusionsGenetic and clinical evidence supports the concept that reduction in LDL‐C levels below current recommended targets may provide additional clinical benefit to patients without adversely impacting patient safety. Statin add‐on therapies, such as ezetimibe and the recently approved proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors alirocumab and evolocumab, allow patients to achieve very low LDL‐C levels and are likely to impact on future treatment paradigms.

Abstract P1-08-02: Metformin blocks de novo synthesis of cholesterol in triple negative breast cancer cells

Abstract Background: Metabolic shifts in cancer and stem cells are well recognized (the so called Warburg Effect). Tumor cells frequently demonstrate alterations in lipid metabolism. The anti-diabetic drug metformin has been shown to have broad anti-cancer activity, reducing both the incidence and mortality of several types of cancer. Metformin inhibits pro-oncogenic cell signaling and metabolic pathways, and has demonstrated unique anti-stem cell activity. We have reported that metformin is particularly active against triple negative (TN) breast cancer cells, inducing S phase arrest and apoptosis. Metformin down regulates de novo fatty acid synthesis, significantly reducing fatty acid synthase (FASN) and FASN protein expression. Mechanistically, these shifts appear secondary to a metformin associated up regulation of miR-193a, which directly targets the FASN 3"UTR (In press, Wahdan-Alaswad et al, Hormones and Cancer). Cancer cells require high cholesterol for membrane synthesis, rigidity, the formation of lipid rafts (membrane regions which organize critical receptor/signaling molecules including the epidermal growth factor receptor (EGFR)), and to provide precursor molecules for hormones and sterols. While de novo cholesterol biosynthesis and high systemic cholesterol levels have been associated with an increase in breast cancer risk and a worse prognosis for women with the disease, clinical studies of statins (drugs to inhibit the mevalonate synthesis pathway and thus block cholesterol synthesis) have shown mixed results. Silvente-Poirot S et al have suggested that the contradictory effects of anti-cholesterol strategies may be due to the complexity of the genes and enzymes controlling the "sterolome" (Science, 2014). Results: The effects of metformin on de novo cholesterol biosynthesis in the TN breast cancer cells, MDA-MB-231 and MDA-MB-468, were studied using expression profiling and miRNA microarrays. Metformin treatment for 24 h down regulated the expression of 21 genes encoding enzymes in the cholesterol biosynthesis pathway at high levels (up to 9 fold), which has been confirmed by qRT-PCR. Metformin treatment for 6 h also resulted in the upregulation of 17 miRNA, which are predicted to control many of the down regulated genes. These data suggest a post-translational inhibition of cholesterol biosynthesis, similar to what we have reported for fatty acid biosynthesis (see above). The down regulated enzymes include critical steps in complex cholesterol biosynthesis pathway occurring in the cytosol, endoplasmic reticulum and the nuclear envelope. Western blots have confirmed that miRNA 141 and miR192 reversed the metformin induced reduction in p-MEK1/2, p-Akt and pMAPK. Conclusions: Metformin regulates cancer cells by multiple pathways including reduction in cell growth, increases in apoptosis and alterations in cellular metabolism. The effects on the cholesterol pathway are both extensive and affect multiple downstream pathways including EGFR, Akt, and MAPK. Partial funding was provided by the Susan G. Komen Foundation. Citation Format: Ann D Thor, Zeying Fan, Reema Wahdan-Alaswad, Steve M Anderson, Jennifer K Richer, Susan M Edgerton. Metformin blocks de novo synthesis of cholesterol in triple negative breast cancer cells [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-08-02.

No Evidence for Statin‐induced Proteinuria in Healthy Volunteers asAssessed by Proteomic Analysis

In clinical studies of statins (class of drugs lowering plasma cholesterol levels), transient low-molecular-weight proteinuria was observed. The causes of statin-induced proteinuria in the patient background of those studies (cardiovascular and kidney disease) are multifactorial and, therefore, a matter of debate. In light of this, it seemed interesting to investigate the effect of statins on the urinary protein concentration and proteome in healthy volunteers. Six healthy volunteers were randomly treated with rosuvastatin (40 mg/day) or pravastatin (80 mg/day) in a double-blinded cross-over study. Total urinary protein concentration and the concentration of albumin/retinol-binding protein were analysed, after which the urinary proteome was investigated. From the results described in this study, it was concluded that statins do not induce major changes in the urinary protein concentration/proteome. High variability in the baseline urinary proteome/proteins among volunteers, however, made it very difficult to find subtle (possibly isolated to individuals) effects of statins.

A meta-analysis of clinical studies of statins for prevention of abdominal aortic aneurysm expansion

A meta-analysis of clinical studies of statins for prevention of abdominal aortic aneurysm expansion

Statins and osteoporosis: new role for old drugs

Osteoporosis is the most common bone disease, affecting millions of people worldwide and leading to significant morbidity and high expenditure. Most of the current therapies available for its treatment are limited to the prevention or slowing down of bone loss rather than enhancing bone formation. Recent discovery of statins (HMG-CoA reductase inhibitors) as bone anabolic agents has spurred a great deal of interest among both basic and clinical bone researchers. In-vitro and some animal studies suggest that statins increase the bone mass by enhancing bone morphogenetic protein-2 (BMP-2)-mediated osteoblast expression. Although a limited number of case-control studies suggest that statins may have the potential to reduce the risk of fractures by increasing bone formation, other studies have failed to show a benefit in fracture reduction. Randomized, controlled clinical trials are needed to resolve this conflict. One possible reason for the discrepancy in the results of preclinical, as well as clinical, studies is the liver-specific nature of statins. Considering their high liver specificity and low oral bioavailability, distribution of statins to the bone microenvironment in optimum concentration is questionable. To unravel their exact mechanism and confirm beneficial action on bone, statins should reach the bone microenvironment in optimum concentration. Dose optimization and use of novel controlled drug delivery systems may help in increasing the bioavailability and distribution of statins to the bone microenvironment. Discovery of bone-specific statins or their bone-targeted delivery offers great potential in the treatment of osteoporosis. In this review, we have summarized various preclinical and clinical studies of statins and their action on bone. We have also discussed the possible mechanism of action of statins on bone. Finally, the role of drug delivery systems in confirming and assessing the actual potential of statins as anti-osteoporotic agents is highlighted.

Potential antitumor effects of statins (Review)

Statins, which have been introduced to the clinic for the treatment of hypercholesterolemia, are competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the major rate-limiting enzyme that controls the conversion of HMG-CoA to mevalonic acid (MA). MA is the precursor in the biosynthesis of isoprenoid compounds including cholesterol, dolichol and ubiquinone. Furthermore, mevalonate-derived prenyl groups enable precise cellular localization and function of many proteins such as Ras and Rho proteins. Therefore, besides lowering cholesterol level, statins exert pleiotropic effects on many essential cellular functions including cell proliferation, differentiation, and survival but also participate in the regulation of cell shape and motility. Statins have been shown to inhibit proliferation and to induce apoptosis in a variety of tumor cells. They have also been found to display antitumor effects against melanoma, mammary carcinoma, pancreatic adenocarcinoma, fibrosarcoma, glioma, neuroblastoma, and lymphoma in animal tumor models resulting in retardation of tumor growth, and/or inhibition of the metastatic process. In preclinical studies statins have also been demonstrated to potentiate the antitumor effects of some cytokines and chemotherapeutics. The molecular mechanisms underlying antitumor activity of statins have not been fully elucidated but interference with the function of Ras and Rho family GTPases, inhibition of the activity of certain cyclin-dependent kinases (CDK), and activation of CDK inhibitors, all seem to participate in this activity. The results of several clinical studies of statins in cancer patients including phase I, phase I/II, and phase II trials have been published. Although evaluation of the therapeutic efficacy is not the purpose of early clinical trials and all conclusions might be premature at this stage, some preliminary conclusions have already been drawn. The results of these studies do not show any significant therapeutic effects of statins in cancer patients. However, the results of one of these studies suggest that statins could effectively strengthen the therapeutic activity of some chemotherapeutics. This observation seems to agree with the results of preclinical studies. However, as toxic side effects of statins have been particularly evident in their combination with some other drugs great caution should be advised while planning clinical trials based on combination therapy including statins in cancer patients.