• chronic inflammation
• chronic kidney disease
• immune dysfunction
• influenza vaccination
• renal cell carcinoma

• Taipei Medical University
• Ministry of Science and Technology

• anticancer activities
• cancer therapy
• clinical application
• signaling pathways
• statins

Hypolipidemic drugs are among the most frequently prescribed medications in the Western world. Since many studies have indicated their role in carcinogenesis, this work aimed to investigate their association with the occurrence of a second primary malignancy in colorectal cancer survivors. The overall incidence of a second neoplasm was not linked to hypolipidemic medication; however, a subgroup analysis revealed a lower incidence of secondary neoplasia in statin users. When stratified by cancer types, a significant increase in gastric and bladder cancer was detected among colorectal cancer patients using hypolipidemic drugs. Survival outcomes in patients with early-stage colorectal carcinoma who suffered second cancer were significantly worse if treated with hypolipidemic drugs. Although our results do not provide evidence for a causative relationship between hypolipidemic medication and carcinogenesis, these correlations might steer the direction of tertiary prevention care towards specific risk factors shared between cardiovascular diseases and cancer.

An increasing number of studies has brought evidence of the protective role of statin use against different types of cancer. However, data on their association with second primary malignancies (SPMs) are lacking. The purpose of this study was to determine the role of hypolipidemic treatment in the prevention of second primary cancer in colorectal cancer (CRC) survivors. We conducted a retrospective single-institution study of 1401 patients with newly diagnosed colorectal cancer from January 2003 to December 2016, with follow-up until December 2020. An SPM was detected in 301 patients (21%), and the incidence was significantly lower in patients with statin medication. However, stratification by cancer types revealed an increased incidence of bladder and gastric cancer in hypolipidemic users. A Kaplan−Meier analysis of early-stage CRC survivors with an SPM showed a significant survival benefit in patients without a history of hypolipidemic treatment. Despite the protective role of statins on overall second cancer incidence, these data indicate that CRC survivors treated with hypolipidemic drugs should be screened more cautiously for SPMs, especially for gastric and bladder cancer.

Statins inhibit 3-hydroxy-3-methylglutaryl-CoA reductase, the rate-limiting enzyme of the mevalonate pathway, and are widely used as an effective and safe approach handle hypercholesterolemia. The mevalonate pathway is a vital metabolic pathway that uses acetyl-CoA to generate isoprenoids and sterols that are crucial to tumor growth and progression. Multiple studies have indicated that statins improve patient prognosis in various carcinomas. Basic research on the mechanisms underlying the antitumor effects of statins is underway. The development of new anti-cancer drugs is progressing, but increasing medical costs from drug development have become a major obstacle. Readily available, inexpensive and well-tolerated drugs like statins have not yet been successfully repurposed for cancer treatment. Identifying the cancer patients that may benefit from statins is key to improved patient treatment. This review summarizes recent advances in statin research in cancer and suggests important considerations for the clinical use of statins to improve outcomes for cancer patients.

• Statin
• HMG CoA reductase inhibitor
• Mevalonate pathway
• Cancer

The importance of statins in cancer has been discussed in many studies. They are known for their anticancer properties against solid tumors of the liver or lung, as well as diffuse cancers, such as multiple myeloma or leukemia. Currently, the most commonly used statins are simvastatin, rosuvastatin and atorvastatin. The anti-tumor activity of statins is largely related to their ability to induce apoptosis by targeting cancer cells with high selectivity. Statins are also involved in the regulation of the histone acetylation level, the disturbance of which can lead to abnormal activity of genes involved in the regulation of proliferation, differentiation and apoptosis. As a result, tumor growth and its invasion may be promoted, which is associated with a poor prognosis. High levels of histone deacetylases are observed in many cancers; therefore, one of the therapeutic strategies is to use their inhibitors. Combining statins with histone deacetylase inhibitors can induce a synergistic anticancer effect.

• anticancer therapy
• cancer
• cancer prevention
• statins

• Cancer
• Drug development
• Drug repurposing
• Statins

• Anticholesteremic Agents/therapeutic use
• Chemoprevention/methods
• Drug Repositioning/methods
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
• Neoplasms/drug therapy
• Research Design

• Department of Health
• C18281/A19169 Cancer Research UK
• 29019 Cancer Research UK
• 26413 Cancer Research UK
• C65320/A26413 Cancer Research UK
• MC_UU_12023/28 Medical Research Council
• 19169 Cancer Research UK

• aspirin
• cancer prevention
• chemoprevention
• colorectal cancer
• vitamins

• Alcohol Drinking/adverse effects
• Allium
• Anti-Inflammatory Agents, Non-Steroidal/administration & dosage
• Antioxidants/administration & dosage
• Aspirin/administration & dosage
• Caffeine
• Coffee
• Colorectal Neoplasms/prevention & control
• Dairy Products
• Dietary Fiber
• Fatty Acids, Omega-3/administration & dosage
• Fish Products
• Folic Acid/administration & dosage
• Fruit
• Garlic
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage
• Magnesium/administration & dosage
• Meat/adverse effects
• Glycine max
• Tea
• Vegetables
• Vitamins/administration & dosage

• Colorectal cancer
• Lipid metabolism
• Liver X receptor
• Nuclear receptor
• Stearoyl-CoA Desaturase

• Colonic Neoplasms
• Fatty Acids
• Humans
• Lipid Metabolism
• Liver X Receptors
• Stearoyl-CoA Desaturase/metabolism

• Anticancer
• Aspirin
• Lung cancer
• Metformin
• Statins

• Aspirin
• Diabetes Mellitus
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
• Lung Neoplasms/drug therapy
• Lung Neoplasms/epidemiology
• Metformin/therapeutic use

Patients living with chronic obstructive pulmonary disease (COPD) are at an increased risk of lung cancer. A common comorbidity of COPD is cardiovascular disease; as such, COPD patients often receive statins. This study sought to understand the association between statin exposure and lung cancer risk in a population-based cohort of COPD patients.

We identified a population-based cohort of COPD patients based on having filled at least three prescriptions for an anticholinergic or short-acting beta-agonist (SABA). We used an array of methods of defining medication exposure including three conventional methods (ever statin exposure, cumulative duration of use, and cumulative dose) and two novel methods (recency-weighted cumulative duration of use and recency-weighted cumulative dose). To assess residual confounding, a negative control exposure was used to test the validity of our results. All exposure variables were time-dependent.

The population-based cohort of COPD had 39,879 patients with mean age of 70.6 (SD: 11.2) years and, of which, 53.5% were female. There were 12,469 patients who received at least one statin prescription. Results from the reference case multivariable analysis indicated a reduced risk from statin exposure (HR: 0.85 (95% CI: 0.73–1.00) in COPD patients, but this result not statistically significant. Using the two recency-weighted modelling approaches, statin exposure was associated with a statistically significant reduction in lung cancer risk (recency-weighted cumulative dose, HR: 0.85 (95% CI: 0.77–0.93) and recency-weighted cumulative duration of use, HR: 0.97 (95% CI: 0.96–0.99). Multivariable analysis incorporating the negative control exposure was not statistically significant (HR: 0.89 (95% CI: 0.75–1.10).

The results of this population-based analysis indicate that statin use in COPD patients may reduce the risk of lung cancer. While the effect was not statistically significantly across all exposure definitions, the overall results support the hypothesis that COPD patients might benefit from statin therapy.

• Administrative data
• Epidemiology
• Health services research
• Pharmacoepidemiology
• Real-world data
• Statins

• Adenoma
• Chemoprevention
• Colorectal Cancer

• U.S. Food and Drug Administration
• cancer
• chemoprevention
• pharmacologic agents

Statins are reported to reduce the risk of cancer, but the results of various published studies have been contradictory. We carried out an umbrella review to provide an overview and understand the strength of evidence, extent of potential biases, and validity of claimed associations between the use of statins and cancer incidence. We comprehensively re-analyzed the data of meta-analyses of randomized controlled trials (RCTs) and observational studies on associations between statin use and cancer incidence. We also assessed the strength of evidence of the re-analyzed outcomes, which were determined from the criteria including statistical significance of the p-value of random-effects, as well as fixed-effects meta-analyses, small study effects, between-study heterogeneity, and a 95% prediction interval. Using a conventional method to assess the significance of meta-analysis (p-value < 0.05), statins had a statistically significant effect on reducing cancer incidence in 10 of 18 types of cancer. When we graded the level of evidence, no cancer type showed convincing evidence, and four cancers (esophageal cancer, hematological cancer, leukemia, and liver cancer) showed suggestive evidence of a preventive effect. There was weak evidence of an association with six cancers, and no significance for the remaining eight cancers. None of the meta-analyses of RCTs on the association of statin and cancer incidence showed a statistical significance. Although there was a preventive effect of statin on cancer incidence in 10 of the 18 cancer types, the evidence supporting the use of statins to reduce cancer incidence was low. Therefore, the associations between statin use and cancer incidence should be carefully considered by clinicians.

• cancer
• meta-analysis
• statin
• umbrella review

• Apoptosis
• Endometrial cancer
• Metformin
• Statin
• mTOR

Breast cancer (BC) is the leading cause of cancer-related mortality in women, only followed by lung cancer. Given the importance of BC in public health, it is essential to identify biomarkers to predict prognosis, predetermine drug resistance and provide treatment guidelines that include personalized targeted therapies. The Hedgehog (Hh) signaling pathway plays an essential role in embryonic development, tissue regeneration, and stem cell renewal. Several lines of evidence endorse the important role of canonical and non-canonical Hh signaling in BC. In this comprehensive review we discuss the role of Hh signaling in breast development and homeostasis and its contribution to tumorigenesis and progression of different subtypes of BC. We also examine the efficacy of agents targeting different components of the Hh pathway both in preclinical models and in clinical trials. The contribution of the Hh pathway in BC tumorigenesis and progression, its prognostic role, and its value as a therapeutic target vary according to the molecular, clinical, and histopathological characteristics of the BC patients. The evidence presented here highlights the relevance of the Hh signaling in BC, and suggest that this pathway is key for BC progression and metastasis.

• Patched-1
• Smoothened
• TNBC
• breast cancer
• clinical trial
• glioma-associated oncogene
• hedgehog
• sonic
• therapeutics

• 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors
• cancer
• meta-analysis
• randomized controlled trials
• statins

• Cholesterol
• Myopathy
• Oxidative stress
• Statins
• Ubiquinone

• Cancer
• Extra-hepatic tissues
• Isoprenoids
• Liver
• Ras
• Rho

Statins purportedly exert anti-tumoral effects on breast cancer. However, the biologic mechanisms for these actions are not fully elucidated. The aims of this study were 1) to explore the effects of simvastatin on apoptosis, proliferation as well as PI3K/Akt/mTOR and MAPK/ERK pathway in a window-of-opportunity breast cancer trial; 2) to further confirm findings from the clinical trial by functional studies; 3) to explore the regulatory role of mevalonate pathway on the anti-tumoral effects of simvastatin. In clinical samples, simvastatin led to increase in cleaved caspase-3 (p = 0.002) and decreased trend for Ki67 (p = 0.245). Simvastatin markedly suppressed PI3K/Akt/mTOR signalling by activating PTEN (p = 0.005) and by dephosphorylating Akt (p = 0.002) and S6RP (p = 0.033); it also inhibited MAPK/ERK pathway by dephosphorylating c-Raf (p = 0.018) and ERK1/2 (p = 0.002). In ER-positive (MCF-7, T47D) and ER-negative (MDA-MB-231, BT-549) breast cancer cells, simvastatin treatment consistently induced apoptosis and inhibited proliferation by deregulating caspase cascades and cell cycle proteins in a dose dependent manner. Concordantly, simvastatin strongly suppressed PI3K/Akt/mTOR pathway by enhancing PTEN expression and by further sequentially dephosphorylating downstream cascades including Akt, mTOR, p70S6K, S6RP and 4E-BP1. Furthermore, simvastatin significantly inhibited MAPK/ERK pathway by dephosphorylating sequential cascades such as c-Raf, MEK1/2 and ERK1/2. These simvastatin anti-tumoral effects were reversed by metabolic products of the mevalonate pathway, including mevalonate, farnesyl pyrophosphate and geranylgeranyl pyrophosphate. These findings shed light on the biological and potential anti-tumoral effects of simvastatin in breast cancer.

• MAPK/ERK
• PI3K/Akt/mTOR
• breast cancer
• mevalonate pathway
• simvastatin

3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, known as statins, are commonly prescribed for the treatment of hypercholesterolemia and cardiovascular disease. A systematic review was conducted using the keywords “statin and prostate cancer” within the title search engines including PubMed, Web of Science, and the Cochrane Library for relevant research work published between 2004 and December 2015. Although still premature, accumulating clinical evidence suggests that statin use may be beneficial in the prevention and/or treatment of prostate cancer. These human studies consist of meta-analyses of secondary endpoints obtained from randomized, controlled cardiovascular disease clinical trials of statins, patient database, observational studies, and a few, small case–control studies, directly addressing statin use on prostate cancer pathology and recurrence. This review summarizes and discusses the recent clinical literature on statins and prostate cancer with a recommendation to move forward with randomized, placebo-controlled clinical trials, investigating the use of statins. Additional preclinical testing of statins on prostate cancer cell lines and in vivo models is needed to elucidate pathways and determine its efficacy for prevention and/or treatment of prostate cancer, more specifically, the difference in the effectiveness of lipophilic versus hydrophilic statins in prostate cancer.

• 3-hydroxy-3-methylglutaryl-coenzyme
• chemoprevention
• cholesterol biosynthesis
• prostate cancer
• prostate-specific antigen
• statins

• Animals
• Antineoplastic Agents/therapeutic use
• Carcinoma, Hepatocellular/drug therapy
• Drug Interactions
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
• Liver Neoplasms/drug therapy
• Palliative Care
• Rats

• Colorectal Neoplasms/diagnosis
• Colorectal Neoplasms/mortality
• Colorectal Neoplasms/prevention & control
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
• Prognosis

• HMG-CoA reductase inhibitor
• carcinogenesis
• case-control study
• colon cancer
• hepatocellular cancer
• pharmacoepidemiology

• clinical outcome prediction
• colon adenocarcinoma
• integrative analysis
• multi-dimensional genomic data
• serous cystadenocarcinoma

• P30 CA014236 NCI NIH HHS

Recent epidemiological studies, basic research and clinical trials on colorectal cancer (CRC) prevention have helped identify candidates for effective chemopreventive drugs. However, because of the conflicting results of clinical trials or side effects, the effective use of chemopreventive drugs has not been generalized, except for patients with a high-risk for developing hereditary CRC. Advances in genetic and molecular technologies have highlighted the greater complexity of carcinogenesis, especially the heterogeneity of tumors. We need to target cells and processes that are critical to carcinogenesis for chemoprevention and treatment of advanced cancer. Recent research has shown that intestinal stem cells may serve an important role in tumor initiation and formation of cancer stem cells. Moreover, studies have shown that the tumor microenvironment may play additional roles in dedifferentiation, to enable tumor cells to take on stem cell features and promote the formation of tumorigenic stem cells. Therefore, early tumorigenic changes of stem cells and signals for dedifferentiation may be good targets for chemoprevention. In this review, I focus on cancer stem cells in colorectal carcinogenesis and the effect of major chemopreventive drugs on stem cell-related pathways.

• Colorectal cancer
• Chemoprevention
• Cancer stem cell
• Carcinogenesis
• Microenvironment

• Adenylate Kinase/metabolism
• Animals
• Anticarcinogenic Agents/therapeutic use
• Bone Morphogenetic Proteins/metabolism
• Cell Differentiation
• Clinical Trials as Topic
• Colorectal Neoplasms/drug therapy
• Humans
• Intestines/cytology
• Metformin/therapeutic use
• Mice
• NF-kappa B/metabolism
• Neoplastic Stem Cells/drug effects
• PPAR gamma/agonists
• Stem Cells/cytology

• cancer
• meta-analysis
• pharmacoepidemiology
• randomized trials
• review

• Antihypertensive Agents/adverse effects
• Antirheumatic Agents/adverse effects
• Bone Density Conservation Agents/adverse effects
• Humans
• Hypoglycemic Agents/adverse effects
• Hypolipidemic Agents/adverse effects
• Meta-Analysis as Topic
• Neoplasms/chemically induced
• Observational Studies as Topic
• Randomized Controlled Trials as Topic
• Risk

The therapeutic indications of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) include hypercholesterolaemia and the prevention of cardiovascular events. Statins are well tolerated and beyond their unambiguous positive cardiovascular effects there are a steadily increasing number of pleiotropic actions emerging. In this regard, growth inhibition, apoptosis, anti-inflammatory and immunomodulatory actions have been attributed to statins. The anti-proliferative effects have been the basis for massive preclinical investigations to elucidate a functional role for statins in carcinogenesis and tumor cell growth. However, preclinical and clinical studies are conflicting, although there is accumulating evidence that statins are capable to suppress and decrease the incidence and recurrence of some human cancers. Given the fact that statins are well tolerated they might also have some impact in combinations with conventional and targeted chemotherapy. While synergism has been shown for many combinations in vitro this does not hold true yet in the clinics. Here we review the rational behind usage of statins in oncological settings. Positive effects have been observed in patients with melanoma and cancers from the breast, colon, prostate, lung, liver and hematologic tissues. However, substantial evidence from clinical studies is still weak and confounded by several factors, which are inherent in the study design. The majority of the studies are observational or of retrospective nature. Definitely, there is substantial need for larger, prospective randomized, placebo-controlled trials. Finally, we conclude that statins at the current status of evidence should not be recommended in the prevention or during progression of any cancers, however, individual statins may have beneficial effects in specific tumor subgroups.

• 3-Hydroxy-3-methylglutaryl-coenzyme A-reductase inhibitors
• Low density lipoprotein cholesterol
• Cancer
• Breast cancer
• Apoptosis
• Statins

• meta-analysis
• prostate cancer
• radical prostatectomy
• radiotherapy
• recurrence
• statin

• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
• Male
• Neoplasm Recurrence, Local/diagnosis
• Neoplasm Recurrence, Local/drug therapy
• Prostatectomy/trends
• Prostatic Neoplasms/diagnosis
• Prostatic Neoplasms/radiotherapy
• Prostatic Neoplasms/surgery

• 5 T32 CA 9001-36 NCI NIH HHS

• Endometrial cancer
• Ovarian cancer
• Risk
• Statins
• Survival

• Adenomatous Polyps/epidemiology
• Aspirin/therapeutic use
• Case-Control Studies
• Confounding Factors, Epidemiologic
• Dose-Response Relationship, Drug
• Female
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
• Incidence
• Intestinal Polyps/epidemiology
• Male
• Middle Aged
• Time Factors
• United Kingdom/epidemiology

• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects
• Lung Neoplasms/complications
• Risk Factors

• Chemoprevention/methods
• Colorectal Neoplasms/prevention & control
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use

• CAF/10/15 Chief Scientist Office
• K24 DK098311 NIDDK NIH HHS
• R01 CA137178 NCI NIH HHS