Differential efficacy of 3-hydroxy-3-methylglutaryl CoA reductase inhibitors on the cell cycle of prostate cancer cells

Members of the statin family of 3-hydroxy-3-methylglutaryl CoA reductase inhibitors are being investigated for the therapy and prevention of cancers because of their growth-inhibitory effects on epithelial cells. Some epidemiologic studies show that patients taking statins show a lower incidence of cancer compared with those taking other cholesterol-lowering medication. In contrast, other studies show that statin use does not correlate with cancer risk. To address this discrepancy, we investigated the efficacy of different statins on the PC-3 prostate cancer cell line and the androgen-dependent LNCaP prostate cancer cell line. Clinically used statins, lovastatin, fluvastatin, and simvastatin inhibit proliferation of the two prostate cancer cells by inducing a G1 arrest. Lovastatin induced the arrest at 0.5 micromol/L, a concentration easily reached in the serum after oral administration. Pravastatin, however, was less effective at inhibiting 3-hydroxy-3-methylglutaryl CoA reductase in PC-3 cells and had to be present at 200 times higher concentrations to effect a cell cycle arrest. Another potential source of variability is the different levels of the cyclin-dependent kinase (cdk) inhibitor p27 noted in prostate cancers particularly because statins have been suggested to act through the induction of cdk inhibitors. All three statins (lovastatin, fluvastatin, and simvastatin) inhibited cyclin E/cdk2 kinase leading to hypophosphorylation of Rb, but this inhibition was correlated with a loss of the activating phosphorylation on Thr160 of cyclin E-associated cdk2 and not dependent on the cdk inhibitors p21 and p27. Therefore, p27 status is unlikely to confound the epidemiologic data on the efficacy of statins in prostate cancer. To make definitive conclusions about the efficacy of statins on cancer prevention, however, the epidemiologic studies should take into account the type of statin used and the serum concentrations achieved and ensure that the tested statin inhibits the specific type of cancer in vitro at those concentrations.     

Lipid-lowering therapy. New and established agents reduce risk of cardiovascular events

Lipid therapy has come a long way in the past 20 years. In the late 1980s, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") were introduced, and they have continued to demonstrate benefits in multiple large-scale primary and secondary prevention trials. A broader understanding of the effects of statin medications has led to new therapeutic goals for different patient populations. In this article, Dr Smith discusses recent developments in statin therapy as well as the introduction of a new class of drugs called selective cholesterol absorption inhibitors.     

Statin pleiotropy: fact or fiction?

Accumulating evidence from clinical trials and basic research indicates that statin therapy favorably influences a number of diverse clinical events through both effects related to lowering of LDL cholesterol levels and effects independent of the lowering of LDL cholesterol levels. The latter effects are referred to as pleiotropic. The full potential of this exciting class of drugs in vascular and nonvascular protection is only just being realized. The pleiotropic effects of the statins improve vascular relaxation, promote new vessel formation, and stabilize unstable plaques. Statins reduce glomerular injury, renal disease progression, insulin resistance, and bone resorption. Ezetimibe, a recently approved medication, enhances the lipid-lowering effects of the statins by lowering LDL and increasing HDL levels through its property of inhibiting absorption of cholesterol in the small intestine. These salutary effects of ezetimibe on statin levels presumably enhance the beneficial effects attributed to statin pleiotropy. It is noteworthy that the pleiotropic properties of the statins have been beneficial in a variety of diseases that involve a number of organs and organ systems. No other therapeutic agent can claim equally stellar results in such a wide variety of diseases. The common denominator in all of the diseases that have been shown to improve with statin pleiotropy could be arteriolar pathology due to hyperlipidemia, which improves in response to statins by a return of arteriolar function to normal rather than through statin pleiotropy. Recent reports indicate that higher doses of statins reverse atheromatous changes in the coronary artery when the LDL cholesterol level is lowered to well below 2.59 mmol/L (100 mg/dL). These results lend additional support to the probability that similar pathological changes that may be present in the small arteries and arterioles also can respond to adequate statin therapy. Statin pleiotropy: fact or fiction?     

Optimizing LDL-C lowering with statins

Clinical studies have demonstrated the efficacy of statins in reducing low-density lipoprotein cholesterol (LDL-C) and lowering coronary heart disease risk. However, many patients receiving statin therapy in clinical practice are not achieving their LDL-C goals. Generally, statins are initiated at starting doses, and doses should be titrated as needed until the goal of therapy is achieved or a second lipid-lowering drug is required; titration is required in the majority of patients who receive less efficacious agents. Most patients receiving statin therapy in clinical practice are maintained on their starting dose, and this frequently results in inadequate control of elevated cholesterol levels. A number of factors may limit dose titration in clinical practice, including the cost of therapy, safety of prescribing statins at high doses and the additional office visits required for evaluations and monitoring. There may be several solutions to this problem. The choice of statin appears to be one of the important factors influencing the success of therapy. Selecting a statin that provides greater LDL-C lowering enables more patients to achieve LDL-C goals, and the majority of patients can be effectively treated with starting doses of the more efficacious statins. Another factor influencing the success of therapy is the willingness to add other drugs to a statin to enhance LDL-C lowering. Choices here include niacin, a bile acid sequestrant, and ezetimibe, a new cholesterol absorption inhibitor. Of these approaches, use of a more efficacious statin is preferred to combination therapy because of cost, safety, effectiveness, and simplicity issues.     

Statins in the intensive care unit

PURPOSE OF REVIEW: Statins are effective lipid-lowering agents used extensively in medical practice. This review summarizes the evidence for statin treatment of cardiovascular patients in the intensive care unit and briefly discusses the role of statins in prevention and treatment of sepsis as a potential future application of statins in critical care. RECENT FINDINGS: Recent studies have extended the use of statin therapy to the acute manifestations of cardiovascular disease and have suggested cholesterol-independent therapeutic benefits, termed pleiotropic effects, which have added a wide scope of potential targets for statin therapy. SUMMARY: Statin therapy should be continued in intensive-care patients in whom statin therapy is warranted due to underlying cardiovascular disease or significant risk thereof. In acute coronary syndromes, statin therapy should be initiated within 24-96 h regardless of pretreatment cholesterol levels. Patients undergoing vascular surgery should receive peri-operative statin therapy. Placebo-controlled clinical trials are required to consolidate the experimental and observational evidence for prevention and treatment of sepsis.     

The role of cholesterol and statins in Alzheimer's disease

OBJECTIVE: To briefly discuss the impact of elevated total and low-density-lipoprotein cholesterol levels, as well as the potential relationship of hydroxymethylglutaryl coenzyme A reductase inhibitor (statin) use, on the development of Alzheimer's disease (AD). DATA SOURCES: Biomedical literature was accessed through MEDLINE and International Pharmaceutical Abstracts (1966-June 2003). The authors independently reviewed literature for possible inclusion in this article. STUDY SELECTION AND DATA EXTRACTION: Clinical studies were selected and reviewed from the data sources, with special emphasis on those dealing with statin use and AD. DATA SYNTHESIS: The impact of AD is significant, as it is rapidly becoming one of our country's most debilitating and costly diseases. Data from epidemiologic trials indicate that statins may have some protective effect against the development of AD. These trials also allude to theories regarding possible mechanisms of action for this use, data implicating possible superiority of one statin over another, and their lack in certain populations, specifically the very old elderly population. CONCLUSIONS: Preliminary evidence suggests that statins may offer a protective effect against the development of AD. However, review of the literature does not lend credence to the use of statins in the general nondemented population without hyperlipidemia. Potential confounding variables have not been considered in the majority of trials. Placebo-controlled clinical trials are ongoing and should yield more definitive results.     

Instant evaluation of contrast enhanced endoscopic ultrasound helps to differentiate various solid pancreatic lesions in daily routine

BACKGROUND Contrast enhanced harmonic endoscopic ultrasound(CEH-EUS) is a spreading technique; some studies have shown its value in the diagnosis of pancreatic adenocarcinoma using quantitative analysis.AIM To examine the value of CEH-EUS for differentiating various pancreatic lesions in everyday routine with qualitative and quantitative analysis.METHODS Data of 55 patients with pancreatic lesions who underwent CEH-EUS were analysed retrospectively. Perfusion characteristics were classified by the investigator qualitatively immediately upon investigation, quantitative analysis was performed later on. Samples from fine needle aspiration(EUS-FNA) or surgical specimen served as gold standard.RESULTS CEH-EUS showed 39 hypoenhanced lesions, 3 non-enhanced and 13 hyperenhanced lesions. Concordance of the investigators qualitative classification of peak contrast enhancement with quantitative analysis later on was 100%, while other parameters such as arrival time, time to peak or area under the curve did not show additional value. 34 of 39 hypoenhanced lesions were pancreatic adenocarcinoma; of the hyperenhanced lesions 4 were inflammatory, 3 neuroendocrine carcinomas, 1 lymphoma, 1 insulinoma and 4 metastases(2 of renal cell carcinoma, 2 of lung cancer). Non-enhanced lesions showed up as necroses. Sensitivity for the detection of pancreatic adenocarcinoma was 100%,specificity 87.2% for hypoenhancement alone; in otherwise healthy pancreatic tissue all hypoenhanced lesions were pancreatic adenocarcinoma(sensitivity and specificity 100%, PPV and NPV for adenocarcinoma 100%).CONCLUSION This study again shows the excellent value of CEH-EUS in everyday routine for diagnostics of various focal pancreatic lesions suggesting that qualitatively assessed hypoenhancement is highly predictive for adenocarcinoma. Additional quantitative analysis of perfusion parameters does not add diagnostic yield. In case of the various hyperenhanced pancreatic lesions in our data set, histologic sampling is essential for further treatment.     

A systematic review and meta‐analysis on the therapeutic equivalence of statins

Background: Statins are the most commonly prescribed agents for hypercholesterolemia because of their efficacy and tolerability. As the number of patients in need of statin therapy continues to increase, information regarding the relative efficacy and safety of statins is required for decision‐making. Objective: This study will use systematic review to compare the efficacy and safety profiles of different statins at different doses and determine the therapeutically equivalent doses of statins to achieve a specific level of low‐density lipoprotein cholesterol (LDL‐C) lowering effect. Methods: Publications of head‐to‐head randomized controlled trials (RCTs) of statins were retrieved from the Oregon state database (1966–2004), MEDLINE (2005‐April of 2006), EMBASE (2005‐April of 2006), and the Cochrane Controlled Trials Registry (up to the first quarter of 2006). The publications were evaluated with predetermined criteria by a reviewer before they were included in the review. The mean change in cholesterol level of each statin was calculated and weighted by number of subjects involved in each RCT. Where possible, meta‐analysis was performed to generate pooled estimates of the cholesterol lowering effect of statins and the difference between statins. Results: Seventy‐five studies reporting RCTs of head‐to‐head comparisons on statins were included. Most studies had similar baseline characteristics, except the rosuvastatin related studies. A daily dose of atorvastatin 10 mg, fluvastatin 80 mg, lovastatin 40–80 mg, and simvastatin 20 mg could decrease LDL‐C by 30–40%, and fluvastatin 40 mg, lovastatin 10–20 mg, pravastatin 20–40 mg, and simvastatin 10 mg could decrease LDL‐C by 20–30%. The only two statins that could reduce LDL‐C more than 40% were rosuvastatin and atorvastatin at a daily dose of 20 mg or higher. Meta‐analysis indicated a statistically significant but clinically minor difference (<7%) between statins in cholesterol lowering effect. Comparisons of coronary heart disease prevention and safety could not be made because of insufficient data. Conclusions: At comparable doses, statins are therapeutically equivalent in reducing LDL‐C.     

Statins in non-ischaemic cardiomyopathy: an update on our current clinical and pathophysiological understanding

Statins are a cornerstone in reducing cardiovascular events. Studies show that statins are beneficial even in patients with normal or low cholesterol levels, indicating pleiotropic mechanisms of therapeutic benefit apart from their antihyperlipidemic effect. Non-randomised, observational and retrospective studies suggest that statins are associated with better outcomes in patients with heart failure (HF) of both ischaemic and non-ischaemic aetiologies. While cholesterol reduction and plaque stabilisation likely play a role in reducing cardiovascular events in ischaemic HF patients, the mechanisms underlying the benefit in non-ischaemic HF patients is less clear. This review suggests the pleiotropic effects of statin therapy can beneficially alter the pathophysiological mechanisms underlying the clinical benefit observed in non-ischaemic HF patients.     

The statin studies: from targeting hypercholesterolaemia to targeting the high-risk patient

The landmark HMG-CoA reductase inhibitor (statin) studies have practical lessons for clinicans. The 4S trial established the importance of treating the hypercholesterolaemic patient with cardiovascular heart disease. Next, WOSCOPS showed the benefit of treating healthy, high-risk hypercholesterolaemic men. CARE, a secondary prevention trial, showed the benefit of treating patients with cholesterol levels within normal limits. This was confirmed by the LIPID trial, another secondary prevention study, which enrolled patients with cholesterol levels 155-271 mg/dl (4-7 mmol/l). The importance of treating patients with established ischaemic heart disease, and those at high risk of developing heart disease, regardless of cholesterol level, was being realized. In the MIRACL trial, hypocholesterolaemic therapy was useful in the setting of an acute coronary syndrome, while the AVERT study showed that aggressive statin therapy is as good as angioplasty in reducing ischaemic events in patients with stable angina. By showing the value of fluvastatin after percutaneous intervention, LIPS confirmed that benefit is a class action of the statins. The HPS randomized over 20 000 patients, and showed beyond doubt the value of statins in reducing cardiovascular events in the high-risk patient. Although PROSPER showed benefit in treating the elderly patients above 70 years, statin therapy in this trial was associated with an increase in cancer incidence. The comparative statin trials, PROVE-IT, REVERSAL, Phase Z of the A to Z, ALLIANCE and TNT, all showed that high-dose statins will better reduce cardiovascular events in the high-risk patient, although the adverse effects of therapy will also be increased. ALLHAT-LLT, ASCOT-LLA and CARDS showed that for statin therapy to demonstrate a significant benefit, hypertensive or diabetic patients must be at sufficiently high risk of cardiovascular events. The emphasis is now on the risk level for developing cardiovascular events, and treatment should target the high-risk group and not the lipid level of the patient. No therapy is free of adverse effect. Treatment of those most at risk will bring the most benefit; treatment of those not at high risk of cardiovascular disease may expose patients who would not benefit much from therapy to its adverse effects.     

MTA1调控HIF-1α/VEGF通路作用于胰腺癌细胞增殖和迁移能力的研究

目的研究肿瘤转移相关蛋白1(MTA1)对胰腺癌细胞增殖、迁移和缺氧诱导因子(HIF-1α)/血管内皮生长因子(VEGF)信号通路的影响。方法采用Western blot检测MTA1在人胰腺癌组织、癌旁组织组织中的表达。采用酶联免疫吸附(ELISA)检测胰腺癌肿瘤细胞系PDAC-1培养上清液中MTA1浓度。然后加入不同浓度(5.0 ng/ml、10.0 ng/ml、15.0 ng/ml、20.0 ng/ml)的外源性MTA1处理胰腺癌肿瘤细胞系PDAC-1 48 h,MTT法检测细胞增殖。采用MTA1(20.0 ng/ml)和YC-1(50μmol/L)分别单独或联合作用于胰腺癌肿瘤细胞系PDAC-1 48 h,MTT法检测细胞增殖;采用划痕法检测细胞迁移能力;24 h时Western blot检测HIF-1α/VEGF信号通路中的关键蛋白HIF-1α和VEGF蛋白的水平。结果 MTA1在胰腺癌组织中的表达显著高于癌旁组织(P <0.05)。胰腺癌肿瘤细胞系PDAC-1自然生长条件下分泌的MTA1水平随着时间的增加在不断增大,48h后浓度为(0.041±0.003) ng/ml与后续研究中加入的外源MTA1浓度相比,可忽略不计。MTA1浓度在5.0~20.0 ng/ml时,从作用第12小时开始能够显著促进胰腺癌肿瘤细胞系PDAC-1的增殖(P <0.05)具有时间和剂量依赖效应。YC-1能够抑制胰腺癌肿瘤细胞系PDAC-1的增殖和迁移能力。MTA1能够促进HIF-1α和VEGF蛋白的表达,而YC-1能够降低MTA1对HIF-1α和VEGF蛋白表达的促进作用。结论 MTA1可以促进胰腺癌肿瘤细胞系PDAC-1的增殖和迁移,且具有时间和浓度依赖效应,其作用机制可能与HIF-1α/VEGF信号通路相关。     

Synchronous concomitant pancreatic acinar cell carcin and gastric adenocarcinoma: A case report and review of literature

BACKGROUNDMultiple primary malignant tumors are two or more malignancies in an individual without any relationship between the neoplasms. In recent years, an increasing number of cases have been reported. However, concomitant primary gastric and pancreatic cancer reported a relatively small incidence, involving no pancreatic acinar cell carcinoma reports. Here, we present the first case of concomitant pancreatic acinar cell carcinoma and gastric adenocarcinoma.CASE SUMMARYA 69-year-old male presented to our department with a history of vomiting, epigastric pain, and weight loss. Imaging revealed space-occupying lesions in the stomach and the tail of the pancreas, respectively. The patient underwent laparoscopic radical gastrectomy and pancreatectomy simultaneously. The pathologies of surgical specimens were completely different: The resected gastric specimen was moderate to poorly differentiated adenocarcinoma, whereas the pancreatic tumor was consistent with acinar cell carcinoma. The patient was treated with six cycles of oxaliplatin and S-1 chemotherapy. As of March 2021, the patient was healthy without any recurrence or metastasis. After thoroughly reviewing the literature on simultaneous pancreatic and gastric cancers at home and abroad, we discussed the clinical characteristics of these rare synchronous double cancers. Most of the cases had undergone surgery and adjuvant chemotherapy, and all of the cases were pathologically confirmed by the postoperative specimen.CONCLUSIONSynchronous pancreatic acinar cells and gastric adenocarcinoma can occur and should be considered when tumors are found in these organs.     

Metachronous pulmonary and pancreatic metastases arising from sigmoid colon cancer: A case report

BACKGROUNDMetachronous pulmonary and pancreatic metastases from colorectal cancer are rare. The diagnosis of pancreatic metastases is difficult and predominantly relies on computed tomography, pathology and immunohistochemistry. Here, we describe the use of next-generation sequencing (NGS) for determination of the origin of metastasis and prognostic prediction of colorectal cancer.CASE SUMMARYA 59-year-old man was diagnosed with sigmoid adenocarcinoma stage IIA (T3N0M0) and underwent surgery in April 2014, followed by XELOX adjuvant chemotherapy. The patient developed pulmonary metastasis in the right upper lung and underwent surgery in May 2016 without further adjuvant chemotherapy. In May 2018, pancreatic metastasis was found and he underwent pancreaticoduodenectomy. After surgery, he was treated with adjuvant S-1 chemotherapy from June 2018 to March 2019. Histopathological review of the specimens from all three lesions indicated consistent patterns characteristic of colon cancer. Concordant gene mutation profiles were observed across the three lesions that included oncogenic driver mutations most frequently seen in colon cancer (e.g., APC, TP53, KRAS and FBXW7). Blood circulating tumor (ct)DNA before adjuvant chemotherapy was undetectable with NGS, suggesting a favorable response to chemotherapy. The patient was alive and well at the latest follow-up visit, achieving a disease-free survival of 17 mo.CONCLUSIONThe genetic profiles of primary tumor, metastases and ctDNA may have clinical value in auxiliary diagnosis, prognosis and therapeutic decision-making.     

The reality of treating dyslipidaemia in patients with coronary heart disease: a primary care survey

Management of hyperlipidaemia in patients with ischaemic heart disease is suboptimal despite the proven benefit of statin therapy. Significant improvement in management has been shown in the EUROASPIRE II study. It is unclear, however, whether such changes have also occurred in primary care. We aimed to evaluate the use of statin therapy by performing a cross-sectional survey of 300 patients with CHD aged >30 years from three general practices. A total of 249 (83%) of the 300 patients had their cholesterol measured and 141 (47%) were on statin therapy; 129 (43% of total) achieved a target cholesterol of <5 mmol/l, of whom 85 (64%) were on statin therapy. Of the remaining 120 patients whose cholesterol exceeded 5 mmol/l, 56 (47%) were on statin therapy Thus 60% (85/141) of those on statin therapy achieved adequate control compared with 40% (44/108) without statins (p<0.008). Those patients with CHD diagnosed on objective evidence were more likely to receive statin therapy (55.5%). Many patients with CHD are still not receiving appropriate secondary prevention. Those on statin therapy are more likely to achieve target levels <5 mmol/l. The average doses of statins vary and are lower than the evidence-based doses used in previous large-scale studies, which may help explain the persistence of failed treatment.     

Severe irritability associated with statin cholesterol-lowering drugs

BACKGROUND: As use of a drug becomes widespread, the full spectrum of its effects becomes clearer. Although a link has been suggested between low or lowered cholesterol and irritability/aggression, less is known about possible links between irritability and statins. AIM: To assess the possible connection of statin usage to severe irritability. DESIGN: Case series. METHODS: Six patients referred or self-referred with irritability and short temper on statin cholesterol-lowering drugs completed a survey providing information on character of behavioural effect, time-course of onset and recovery, and factors relevant to drug adverse effect causality. RESULTS: In each case the personality disruption, once evident, was sustained until statin use was discontinued; and resolved promptly with drug cessation. In four patients, re-challenge with statins occurred, and led to recrudescence of the problem. All patients experienced other recognized statin adverse effects while on the drug. Manifestations of severe irritability included homicidal impulses, threats to others, road rage, generation of fear in family members, and damage to property. DISCUSSION: Case series invariably raise more questions than they can answer. These case reports suggest that severe irritability may occur in some statin users. Although this adverse effect may be rare, potentially life-threatening adverse effects of drugs must be taken seriously.     

The role of protein kinases in pancreatic carcinogenesis

BACKGROUND: Pancreatic cancer is a devastating disease with a very poor prognosis. METHODS: Protein kinases are aberrantly expressed in pancreatic ductal adenocarcinoma as analyzed by microarray-based expression analysis and have an impact for pancreatic cancer. Many regulatory proteins have an impact on cancer progression similar to the kinases. The list contains several regulators of kinases derived from the cell cycle control or the mitogen-activated protein (MAP)-kinase pathway. CONCLUSION: Both signalling pathways are essential for tumor progression and pancreatic ductal adenocarcinoma (PDAC) malignancy.