Statins in risk-reduction and treatment of cancer

Statins, which are competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, reduce cholesterol blood levels and the risk of developing cardiovascular diseases and their related complications. In addition to this main activity, statins show pleiotropic effects such as antioxidant, anti-inflammatory and antiproliferative properties, with applications in many pathologies. Based on their antiproliferative properties, in vitro and in vivo studies have investigated their effects on various types of cancer (i.e., breast cancer, prostate cancer, colorectal cancer, ovarian cancer, lung cancer) with different genetic and molecular characteristics. Many positive results were obtained, but they were highly dependent on the physiochemical properties of the statins, their dose and treatment period. Combined therapies of statins and cytotoxic drugs have also been tested, and synergistic or additive effects were observed. Moreover, observational studies performed on patients who used statins for different pathologies, revealed that statins reduced the risk of developing various cancers, and improved the outcomes for cancer patients. Currently, there are many ongoing clinical trials aimed at exploring the potential of statins to lower the mortality and the disease-recurrence risk. All these results are the foundation of new treatment directions in cancer therapy.     

Cholesterol-lowering drugs and colorectal cancer incidence in a large United States cohort

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, commonly known as statins, account for most cholesterol-lowering drug use in the United States. A recent large case-control study reported that use of statins for more than 5 years was associated with a 47% reduction in risk of colorectal cancer. No other large studies have examined this association. We examined the association between use of cholesterol-lowering drugs and colorectal cancer incidence among 132,136 men and women in the Cancer Prevention Study II Nutrition Cohort. We identified 815 incident cases of colorectal cancer among study participants during follow-up from the date of completion of a study questionnaire in 1997 through August 31, 2001. Current use of cholesterol-lowering drugs was not associated with colorectal cancer incidence (multivariable adjusted rate ratio [RR] = 1.03, 95% confidence interval [CI] = 0.85 to 1.26). Current use of cholesterol-lowering drugs for 5 years or more was also not associated with colorectal cancer incidence (multivariable adjusted RR = 1.09, 95% CI = 0.83 to 1.43). Our results do not support the hypothesis that statin use strongly reduces risk of colorectal cancer. However, we cannot rule out a small reduction in risk or an effect associated with only specific types or doses of statins.     

Selected Statins as Dual Antiproliferative-Antiinflammatory Compounds

Background: We hypothesized that superlative dual cytotoxicity-antiinflammtion bioefficacies of 9 selected lipophilic statins correlate to their chelation effect of 3,5-dihydroxyheptanoic acid. Methodology: Lipophilic-acid chelating statins have been screened for in vitro duality of proliferation inhibition and NO-radical scavenging capacities. Results: Their spectrum of selectivity indices for safety in PDL fibroblasts -based 72h incubations was reported. Surprisingly despite its lack on macrophages LPS-triggered inflammation over 5-200 µM and unlike the 8 statins; cerivastatin had growth inhibition IC50 values of 40nM (SW620), 110nM (HT29), 2.9 µM (HCT116), 6µM (SW480), and most notably 38µM (<50 µM, in Caco2). Exclusively cerivastatin exerted antitumorigenesis IC50 values <50 µM in all T47D, MCF7 and PANC1 72h cultures. In statins with greater antiinflammation affinity than indomethacin’s; lovastatin had cytotoxicity IC50 values <20 µM in SW62050µM in T47D, MCF7 and PANC1; pravastatin had viability reduction IC50 values <50µM in HT2950 µM were for statins in remaining colorectal cancer cell lines, breast cancer and pancreatic cancer cell lines.Conclusion: Among the rest, cerivastatin warrants further novel scaffold development to maximize efficacy and optimal molecular action mechanisms of chemotherapy/prevention.     

Environmental Exposure and Tumor Heterogeneity in Colorectal Cancer Risk and Outcomes

Colorectal cancers are a group of heterogeneous disorders that involve interactions among environmental influences, germ-line susceptibility factors, and accumulated genetic and epigenetic changes in the colorectal epithelium. This review provides background on environmental exposure and molecular pathways during colorectal cancer pathogenesis. Additionally, the review discusses the interplay between these risk factors in the context of colorectal cancer development and progression. Smoking, obesity, and regular aspirin use appear to have profound effects on colorectal cancer initiation and prognosis through the activation of pathways targeting gene methylation, inflammation, insulin mitogenesis, and cell proliferation. New data on other types of exposure and molecular changes will continue to improve our understanding of the cause of colorectal cancer, leading to novel therapeutic and preventive strategies and ultimate reduction in disease burden.     

Statins are logical candidates for overcoming limitations of targeting therapies on malignancy: their potential application to gastrointestinal cancers

Purpose

Molecular targeting approaches have been an intensive focus of treatment strategies against advanced gastric and colorectal cancers. Recent clinical trials have demonstrated promising survival prolongation of targeted human epidermal growth factor receptors; however, patients harboring mutations in the K-Ras gene (human homolog of the Kirsten rat sarcoma-2 virus oncogene) do not derive benefit from the anti-epidermal growth factor receptor antibodies. K-Ras mutations cause a stimuli-independent activation of a large cohort of downstream effectors that permit cells to acquire a sustained growth. The perpetuated growth activation manifests resistance to molecular targeting therapies.

Methods

Literature review has been made to explore the possibilities that, given that K-Ras or downstream effector proteins require farnesyl or geranylgeranyl moiety for their activity (e.g., prenylation), statins are logical candidates to overcome the limitations of or to potentiate the effect of molecular targeting therapies as statins suppress the mevalonate pathway leading to depletion of an end product of mevalonate such as farnesylpyrophosphate and geranylgeranylpyrophosphate, which are used as substrates by their respective transferase enzyme for protein prenylation, and ultimately impair functions of K-Ras and downstream effector proteins.

Results

In the last few years, statins have gained interest in therapeutic value for anticancer treatments extending beyond their lipid-lowering effects as single agents or in combined use with other chemotherapeutic agents. This review provides insights into possible anticancer mechanisms of statins and introduces current achievements or ongoing studies of statins in the field of cancer treatment in single or combined uses. This review also offers information to help establish optimal treatment schedules of statins that overcome current limitations of molecular targeting therapies.

Conclusions

It is expected that therapeutic scope of statins will expand considerably in the future as anticancer agents in addition to their proven benefits of hyperlipidemia.     

Combination regimen with statins and NSAIDs: a promising strategy for cancer chemoprevention

Statins and nonsteroidal antiinflammatory drugs (NSAIDs) are commonly prescribed for lowering cholesterol and anti-inflammation, respectively. Recently, their potential roles as cancer chemopreventive agents have been subject to intensive studies. Human trials have not provided conclusive results on the protective effects of statins against different cancers, while more convincing results have been observed for cancer preventive effects of NSAIDs, especially on colorectal cancer. A promising strategy to enhance the cancer preventive efficacy of statins and NSAIDs is to use them in combination, which may produce synergy and lower the dose required for each agent. This strategy is of particular interest for potential use of low doses of statins and NSAIDs on a long-term basis for cancer chemoprevention; increased risks for gastrointestinal and cardiovascular side effects associated with the use of NSAIDs have been observed in colorectal cancer chemopreventive trials. This article reviews the evidence for the cancer preventive actions of statins and NSAIDs, as well as their possible synergistic action and the mechanisms involved.     

Role of netrin-1 and netrin-1 dependence receptors in colorectal cancers

Although cancer is a multifaceted disease, all cancer types share identical molecular and cellular mechanisms. These mechanisms involve a collection of alterations critical to the normal physiological functioning of cells, such as alterations of growth factor signalling pathways, angiogenesis, cell adhesion signals, DNA replication and apoptotic cell death. Many genes involved in the processes enumerated above are functionally inactive in tumour cells, designating them as putative 'tumour suppressor genes'. Back in the early 1990s, Vogelstein and colleagues suggested that a gene called DCC (for Deleted in Colorectal Cancer) could be a tumour suppressor gene because it was found to be deleted in more than 70% of colorectal cancers, as well as in many other cancers. During the last 15 years, controversial data have failed to firmly establish whether DCC is indeed a tumour suppressor gene. However, the recent observations that DCC triggers cell death and is a receptor for netrin-1, a molecule recently implicated in colorectal tumorigenesis, have prompted a renewal of interest in the role of DCC in tumorigenesis and suggest that the netrin-1/receptor pairs act as novel negative regulators of tumour development.     

Therapy insight: Potential of statins for cancer chemoprevention and therapy

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, are commonly prescribed medications that lower serum cholesterol and decrease cardiac morbidity and mortality. These agents inhibit the rate-limiting step of the mevalonate pathway, an effect that influences cholesterol homeostasis and other diverse cellular functions. Preclinical data suggest statins have pleiotropic antineoplastic effects in a variety of tumors, but clinical studies have provided conflicting data regarding whether statins may increase or decrease the risk of cancer. Abnormal cholesterol metabolism in cancer is poorly understood but should be considered when evaluating the antineoplastic effects of statins. Emerging evidence suggests that atherosclerosis and cancer have similar underlying molecular mechanisms, both having lipid abnormalities and a pro-inflammatory phenotype. Like nonsteroidal anti-inflammatory agents, statins target lipid metabolism, have significant anti-inflammatory effects, and can influence cardiovascular mortality. Recent studies show that statins may have chemopreventive effects and may complement cytotoxic chemotherapy or radiotherapy as a biologic response modifier in established cancer, but current data do not support their use as monotherapy. The preclinical data supporting anticancer activity, their additional health benefits, and the safety and relative low cost of statins compared to other 'targeted' agents currently under development all favor conducting prospective clinical trials of these drugs in cancer chemoprevention and therapy.     

Statin use and cancer risk: an epidemiologic review

While the beneficial effects of hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) on cardiovascular disease are well established, much uncertainty remains about their effects on cancer. The statins inhibit the rate-limiting step in the mevalonate pathway, leading to reduced levels of cholesterol and other molecules of importance for critical cellular processes. A growing body of preclinical data indicates that statins may have antineoplastic properties, but some studies raise the possibility that statins may possess a carcinogenic potential. Clinical and observational studies of the association between statin use and cancer have been inconclusive with regard to any chemopreventive or therapeutic effect, but they do provide reassuring evidence that statins do not appear to be carcinogenic. The reasons for the varying results are unclear but they may relate to methodological issues. Additional studies, including Phase II randomized trials and epidemiological studies with accurate measures of statin use and comprehensive control for confounding factors, are needed to determine the potentially beneficially effects of statins on cancer development and progression.     

结直肠癌组织中EZH2和SMYD3蛋白表达情况及相关性

目的:检测EZH2和SMYD3蛋白在结直肠癌组织中的表达,分析EZH2和SMYD3蛋白的表达情况与结直肠癌不同病理特征及预后的相关性,探讨EZH2和SMYD3蛋白在结直肠癌发生发展中作用相关性,为结直肠癌的诊断、治疗及预后判断提供全新的分子标志及靶点。方法:结直肠癌组织（实验组）及癌旁组织（对照组）标本取自郑州大学附属肿瘤医院普外科结直肠癌患者根治术后石蜡包埋标本,共60例。采用免疫组织化学方法检测结直肠癌组织及癌旁组织中EZH2和SMYD3蛋白表达情况,结合结直肠癌患者的术后病理,根据2017版NCCN指南完成TNM分期,用χ2检验分析EZH2和SMYD3蛋白在结直肠癌组织及癌旁组织中的表达差异,分析EZH2和SMYD3蛋白表达情况与结直肠癌术后病理参数之间的关系;用Kaplan-Meier法、Log-rank 检验分析EZH2和SMYD3蛋白与结直肠癌患者根治术后无病生存期（DFS）及总生存期（OS）之间的关系,采用Pearson相关性分析EZH2和SMYD3蛋白在结直肠癌组织中表达的相关性。结果:EZH2及SMYD3蛋白在结直肠癌组织中的阳性率明显高于癌旁组织,表明两者均在结直肠癌的发展中表达上调。EZH2蛋白表达情况与肿瘤TNM分期、有无淋巴结转移有显著相关性,SMYD3蛋白表达情况与肿瘤TNM分期、有无淋巴结转移、肿瘤发生部位有显著相关性,表明两者的表达可能与结直肠癌的侵袭和转移有关。 EZH2、SMYD3蛋白表达阳性结直肠癌患者术后DFS较短,表明两者的表达可能提示结直肠癌患者预后不良。在结直肠癌组织中,EZH2、SMYD3蛋白的表达情况呈正相关关系,表明两者在结直肠癌的发生发展过程中可能呈协同作用。结论:EZH2、SMYD3蛋白在结直肠癌组织中的表达上调,在结直肠癌组织表达中呈明显正相关,并且与结直肠癌的不良预后相关,可能会是结直肠癌患者重要的预后因子及治疗靶点。     

Statin use and colorectal cancer risk according to molecular subtypes in two large prospective cohort studies

Use of statins is hypothesized to reduce colorectal cancer risk but the evidence remains inconsistent. This may be partly explained by differential associations according to tumor location or molecular subtypes of colorectal cancer. We examined the association between statin use and colorectal cancer risk according to tumor location, KRAS mutation status, microsatellite instability (MSI) status, PTGS2 (COX-2) expression, or CpG island methylator phenotype (CIMP) status in two large prospective cohort studies, the Nurses' Health Study and Health Professionals Follow-up Study. We applied Cox regression to a competing risks analysis. We identified 1,818 colorectal cancers during 1990 to 2006. Compared with nonusers, current statin use was not associated with colorectal cancer [relative risk (RR) = 0.99, 95% CI = 0.86-1.14] or colon cancer (RR = 1.10, 95% CI = 0.94-1.29) but was inversely associated with rectal cancer (RR = 0.59, 95% CI = 0.41-0.84, P(heterogeneity) < 0.001). When we examined the association within strata of KRAS mutation status, we found no association with KRAS-mutated cancers (RR = 1.20, 95% CI = 0.87-1.67) but did observe a possible inverse association among KRAS wild-type cancers (RR = 0.80, 95% CI = 0.60-1.06, P(heterogeneity) = 0.06). The association did not substantially differ by PTGS2 expression, MSI status, or CIMP status. Current statin use was not associated with risk of overall colorectal cancer. The possibility that statin use may be associated with lower risk of rectal cancer or KRAS wild-type colorectal cancer requires further confirmation.     

Evaluation of Adjuvant Chemotherapy-Associated Steatosis (CAS) in Colorectal Cancer

Chemotherapy-associated steatosis is poorly understood in the context of colorectal cancer. In this study, Stage II–III colorectal cancer patients were retrospectively selected to evaluate the frequency of chemotherapy-associated steatosis and to determine whether patients on statins throughout adjuvant chemotherapy develop chemotherapy-associated steatosis at a lower frequency. Baseline and incident steatosis for up to one year from chemotherapy start date was assessed based on radiology. Of 269 patients, 76 (28.3%) had steatosis at baseline. Of the remaining 193 cases, patients receiving adjuvant chemotherapy (n = 135) had 1.57 (95% confidence interval [CI], 0.89 to 2.79) times the adjusted risk of developing steatosis compared to patients not receiving chemotherapy (n = 58). Among patients who underwent chemotherapy, those using statins for pre-existing hyperlipidemia (n = 37) had 0.71 (95% CI, 0.10 to 2.75) times the risk of developing steatosis compared to patients who were not prevalent users of statins (n = 98). Chemotherapeutic treatment of Stage II–III colorectal cancer appears to be consistent with a moderately increased risk of steatosis, although larger studies are necessary to assess the significance of this observation. Prospective trials should be considered to further explore the potential for protective use of statins in this curative patient population.     

β3 Integrin and Src facilitate transforming growth factor-β mediated induction of epithelial-mesenchymal transition in mammary epithelial cells

Introduction  

Transforming growth factor (TGF)-β suppresses breast cancer formation by preventing cell cycle progression in mammary epithelial cells (MECs). During the course of mammary tumorigenesis, genetic and epigenetic changes negate the cytostatic actions of TGF-β, thus enabling TGF-β to promote the acquisition and development of metastatic phenotypes. The molecular mechanisms underlying this conversion of TGF-β function remain poorly understood but may involve signaling inputs from integrins.     

Statin induces apoptosis and cell growth arrest in prostate cancer cells.

Statins are a class of low molecular weight drugs that inhibit the rate-limiting enzyme of the mevalonate pathway 3-hydroxy-3-methylglutaryl-CoA reductase. Statins have been approved and effectively used to control hypercholesterolemia in clinical setting. Recent study showed statin's antitumor activity and suggested a potential role for prevention of human cancers. In this study, we did cell viability, DNA fragmentation, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assays to evaluate the action of statins on prostate cancer cells and used Western blotting and RhoA activation assay to investigate the underlying molecular mechanism of action. Our data showed that lovastatin and simvastatin effectively decreased cell viability in three prostate cancer cell lines (PC3, DU145, and LnCap) by inducing apoptosis and cell growth arrest at G(1) phase. Both lovastatin and simvastatin induced activation of caspase-8, caspase-3, and, to a lesser extent, caspase-9. Both statins suppressed expression of Rb, phosphorylated Rb, cyclin D1, cyclin D3, CDK4, and CDK6, but induced p21 and p27 expression in prostate cancer cells. Furthermore, lovastatin and simvastatin suppressed RhoA activation and c-JUN expression, but not cyclooxygenase-2 expression. Our data showed that the antitumor activity of statins is due to induction of apoptosis and cell growth arrest. The underlying molecular mechanism of statin's action is mediated through inactivation of RhoA, which in turn induces caspase enzymatic activity and/or G(1) cell cycle. Future studies should focus on examining statins and other apoptosis-inducing drugs (e.g., cyclooxygenase-2 inhibitors or curcumin) together to assess their efficacy in prevention of prostate cancer.     

Hsp60 and Hspl0 as antitumor molecular agents

The molecular chaperones Hsp60 and Hsp10 are, according to recent reports, involved in cancer development and progression. We, for instance, have found that their expression varies with distinctive patterns in different malignancies: they are overexpressed in colorectal, exocervical and prostate carcinogenesis, and colorectal cancer progression, but they are downregulated during bronchial carcinogenesis. There is also evidence showing that Hsp60 and Hsp10 can be used as therapeutic agents, for example in rheumatoid arthritis. In view of these findings we want now to call attention to the potential of Hsp60 and Hsp10 in cancer therapy.     

结直肠癌应用他汀类药物治疗作用机制的研究进展

结直肠癌(CRC)是世界范围内常见的恶性肿瘤之一,发病率居第三位,死亡率居第四位.早期症状不典型,晚期预后差.因此,寻找一种新型的防治CRC的药物势在必行.他汀类药物(statins)属于一种羟甲基戊二酸单酰辅酶A还原酶抑制剂,临床中应用于心脑血管疾病,效果显著.近来有研究表明statins与CRC之间存在着密切联系.他汀类药物可能作为化学治疗结直肠癌的新药物.本文主要对CRC应用statins在阻滞细胞增殖、促进肿瘤细胞凋亡、抗侵袭转移及抑制肿瘤血管形成等方面的作用机制进行全面的总结与阐述.     

The role of inflammation in the pathogenesis of colorectal cancer

Chronic inflammatory disorders are often associated with an increased risk of developing cancer. A classic example of the connection between inflammation and cancer is the increased risk of colorectal cancer in patients with inflammatory bowel disease (IBD). In this review, we discuss aspects of IBD that promote colorectal cancer and highlight key molecular mediators that contribute to cancer risk. Additionally, we report on progress in identifying molecular targets that may prove efficacious in blocking the progression of IBD-related inflammation to cancer.     

Ibuprofen disrupts a WNK1/GSK3β/SRPK1 protein complex required for expression of tumor-related splicing variant RAC1B in colorectal cells

A major risk factor promoting tumor development is chronic inflammation and the use of nonsteroidal anti-inflammatory drugs (NSAID), including ibuprofen, can decrease the risk of developing various types of cancer, including colorectal cancer (CRC). Although the molecular mechanism behind the antitumor properties of NSAIDs has been largely attributed to inhibition of cyclooxygenases (COXs), several studies have shown that the chemopreventive properties of ibuprofen also involve multiple COX-independent effects. One example is its ability to inhibit the alternative splicing event generating RAC1B, which is overexpressed in a specific subset of BRAF-mutated colorectal tumors and sustains cell survival. Here we describe the mechanism by which ibuprofen prevents RAC1B alternative splicing in a BRAF mutant CRC cell line: it leads to decreased translocation of SRPK1 and SRSF1 to the nucleus and is regulated by a WNK1/GSK3β/SRPK1 protein kinase complex. Surprisingly, we demonstrate that ibuprofen does not inhibit the activity of any of the involved kinases but rather promotes disassembly of this regulatory complex, exposing GSK3β serine 9 to inhibitory phosphorylation, namely by AKT, which results in nuclear exclusion of SRPK1 and SRSF1 hypophosphorylation. The data shed new light on the biochemical mechanisms behind ibuprofen’s action on alternative spliced RAC1B and may support its use in personalized approaches to CRC therapy or chemoprevention regimens.     

microRNA在结直肠癌中的研究进展

microRNA（miRNA）是一类长21-25nt核苷酸的内源性非编码调控RNA,通过与靶细胞mRNA的3＇UTR完全互补导致mRNA降解,或不完全互补结合阻断mRNA翻译,参与细胞发育、增殖、分化和凋亡。miRNA具有癌基因和抑癌基因的作用,若干miRNA直接或间接参与结直肠癌的发生和发展,miRNA表达谱与结直肠癌的诊断、分期、进展和预后密切相关。     

Statins and cancer: Current and future prospects

Statins are inhibitors of 3-hydroxy-methylglutaryl (HMG) CoA reductase. They exhibit effects beyond cholesterol reduction, including anticancer activity. This review presents the effects of statins in vitro and their possible molecular anticancer mechanisms and critically discusses the data regarding the role of statins in cancer prevention. Finally, this review focuses on the use of statins combined with other chemotherapeutics to increase the effectiveness of cancer treatments. Despite rare and inconclusive clinical data, the preclinical results strongly suggest that such combined treatment could be a promising new strategy for the treatment of certain tumor types.