Statins In Cancer Research Articles

New insights into the therapeutic potentials of statins in cancer.

The widespread clinical use of statins has contributed to significant reductions of cardiovascular morbidity and mortality. Increasing preclinical and epidemiological evidences have revealed that dyslipidemia is an important risk factor for carcinogenesis, invasion and metastasis, and that statins as powerful inhibitor of HMG-CoA reductase can exert prevention and intervention effects on cancers, and promote sensitivity to anti-cancer drugs. The anti-cancer mechanisms of statins include not only inhibition of cholesterol biosynthesis, but also their pleiotropic effects in modulating angiogenesis, apoptosis, autophagy, tumor metastasis, and tumor microenvironment. Moreover, recent clinical studies have provided growing insights into the therapeutic potentials of statins and the feasibility of combining statins with other anti-cancer agents. Here, we provide an updated review on the application potential of statins in cancer prevention and treatment and summarize the underneath mechanisms, with focuses on data from clinical studies.

Crosstalk between Statins and Cancer Prevention and Therapy: An Update.

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.

Recent Advances of WEE1 Inhibitors and Statins in Cancers With p53 Mutations.

p53 is among the most frequently mutated tumor suppressor genes given its prevalence in >50% of all human cancers. One critical tumor suppression function of p53 is to regulate transcription of downstream genes and maintain genomic stability by inducing the G1/S checkpoint in response to DNA damage. Tumor cells lacking functional p53 are defective in the G1/S checkpoint and become highly dependent on the G2/M checkpoint to maintain genomic stability and are consequently vulnerable to Wee1 inhibitors, which override the cell cycle G2/M checkpoint and induce cell death through mitotic catastrophe. In addition to the lost tumor suppression function, many mutated p53 (Mutp53) proteins acquire gain-of-function (GOF) activities as oncogenes to promote cancer progression, which manifest through aberrant expression of p53. In cancer cells with GOF Mutp53, statins can induce CHIP-mediated degradation of Mutp53 within the mevalonate pathway by blocking the interaction between mutp53 and DNAJA1. Therefore, targeting critical downstream pathways of Mutp53 provides an alternative strategy for treating cancers expressing Mutp53. In this review, we summarize recent advances with Wee1 inhibitors, statins, and mevalonate pathway inhibitors in cancers with p53 mutations.

The Innovative Potential of Statins in Cancer: New Targets for New Therapies.

Numerous and different types of cancers possess the dysregulation of the mevalonate pathway as a common feature. Statins, traditionally applied in cardiovascular diseases to reduce lipid levels, subsequently have been discovered to exhibit anti-cancer activities also. Indeed, statins influence proliferation, migration, and survival of cancer cells by regulating crucial signaling proteins, such as Rho, Ras, and Rac. Recently, several studies have demonstrated that simvastatin, fluvastatin, and lovastatin are implicated in different pathways that enhance the survival time of patients with cancer under treatment in combination with antineoplastic agents. In this minireview, we present an overview of the most important studies conducted regarding the use of statins in cancer therapy up to date.

The Impact of Statin Therapy on the Survival of Patients with Gastrointestinal Cancer.

Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that may play an important role in the evolution of cancers, due to their effects on cancer cell metabolism. Statins affect several potential pathways, including cell proliferation, angiogenesis, apoptosis and metastasis. The number of trials assessing the putative clinical benefits of statins in cancer is increasing. Currently, there are several trials listed on the global trial identifier website clinicaltrials.gov. Given the compelling evidence from these trials in a variety of clinical settings, there have been calls for a clinical trial of statins in the adjuvant gastrointestinal cancer setting. However, randomized controlled trials on specific cancer types in relation to statin use, as well as studies on populations without a clinical indication for using statins, have elucidated some potential underlying biological mechanisms, and the investigation of different statins is probably warranted. It would be useful for these trials to incorporate the assessment of tumour biomarkers predictive of statin response in their design. This review summarizes the recent preclinical and clinical studies that assess the application of statins in the treatment of gastrointestinal cancers with particular emphasize on their association with cancer risk.

Protective Effects of Statins in Cancer: Should They Be Prescribed for High-Risk Patients?

Statins are one of the most widely prescribed drug classes in the USA. This review aims to summarize recent research on the relationship between statin use and cancer outcomes, in the context of clinical guidelines for statin use in patients with cancer or who are at high risk for cancer. A growing body of research has investigated the relationship between statins and cancer with mixed results. Cancer incidence has been more extensively studied than cancer survival, though results are inconsistent as some large meta-analyses have not found an association, while other studies have reported improved cancer outcomes with the use of statins. Additionally, two large studies reported increased all-cancer survival with statin use. Studies on specific cancer types in relation to cancer use have also been mixed, though the most promising results appear to be found in gastrointestinal cancers. Few studies have reported an increased risk of cancer incidence or decreased survival with statin use, though this type of association has been more commonly reported for cutaneous cancers. The overall literature on statins in relation to cancer incidence and survival is mixed, and additional research is warranted before any changes in clinical guidelines can be recommended. Future research areas include randomized controlled trials, studies on specific cancer types in relation to statin use, studies on populations without clinical indication for statins, elucidation of underlying biological mechanisms, and investigation of different statin types. However, studies seem to suggest that statins may be protective and are not likely to be harmful in the setting of cancer, suggesting that cancer patients who already take statins should not have this medication discontinued.

Efectos de las estatinas en cáncer: ¿potencial rol en terapéutica y prevención?

This review explores the evidence supporting a potential benefit of statins in cancer. In particular, the lipophilic forms (i.e. lovastatin, simvastatin, or similar) would have a therapeutic but not a preventive role. The pleiotropic effects that statins possess mainly explain this phenomenon, influencing the natural history of disease and the response to currently available therapies. By inhibiting the mevalonate pathway, statins would have a systemic effect, similar to that observed in atherosclerosis, reducing the inflammatory stimuli present in the tumor micro-environment and inhibiting the activation of intracellular signaling cascades critical for proliferation, migration/invasion and metastasis of the cancer cell. Despite all this evidence, randomized trials are needed to confirm the benefit of statins on cancer, before promoting their widespread use as a therapeutic or preventive strategy for this condition.

Pharmacological Actions of Statins: A Critical Appraisal in the Management of Cancer

Statins, among the most commonly prescribed drugs worldwide, are cholesterol-lowering agents used to manage and prevent cardiovascular and coronary heart diseases. Recently, a multifaceted action in different physiological and pathological conditions has been also proposed for statins, beyond anti-inflammation and neuroprotection. Statins have been shown to act through cholesterol-dependent and -independent mechanisms and are able to affect several tissue functions and modulate specific signal transduction pathways that could account for statin pleiotropic effects. Typically, statins are prescribed in middle-aged or elderly patients in a therapeutic regimen covering a long life span during which metabolic processes, aging, and concomitant novel diseases, including cancer, could occur. In this context, safety, toxicity, interaction with other drugs, and the state of health have to be taken into account in subjects treated with statins. Some evidence has shown a dichotomous effect of statins with either cancer-inhibiting or -promoting effects. To date, clinical trials failed to demonstrate a reduced cancer occurrence in statin users and no sufficient data are available to define the long-term effects of statin use over a period of 10 years. Moreover, results from clinical trials performed to evaluate the therapeutic efficacy of statins in cancer did not suggest statin use as chemotherapeutic or adjuvant agents. Here, we reviewed the pharmacology of the statins, providing a comprehensive update of the current knowledge of their effects on tissues, biological processes, and pathological conditions, and we dissected the disappointing evidence on the possible future use of statin-based drugs in cancer therapy.

Potential immunologic effects of statins in cancer following transplantation.

3-hydroxy-3-methyglutaryl CoA reductase inhibitors (statins) are frequently used following organ transplantation and have well reported pleiotropic effects, including immunomodulation, which may be of benefit in preventing graft rejection. However, the immunomodulatory effects of statins on cell transformation and malignancy, combined with the immunologic processes and administration of immunosuppression are almost completely unknown. The administration of immunosuppression is well recognised as the main cause of cancer following transplantation, so the addition of an immunomodulatory agent should be associated with an increased incidence of cancer, as immune surveillance and response may be suppressed, allowing cellular transformation and proliferation combined with lack of recognition to occur. This hypothetical review attempts to delineate the mode of action of statins in terms of pro/anti-carcinogenic mechanisms, while considering graft rejection and the presence of immunosuppression.

Tocotrienols potentiate lovastatin-mediated growth suppression in vitro and in vivo.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase is the rate-limiting enzyme in the mevalonate pathway that provides essential intermediates for the membrane anchorage and biologic functions of growth-related proteins. Contrary to preclinical studies showing the growth-suppressive activity of statins, competitive inhibitors of HMG CoA reductase, clinical application of statins in cancer is precluded by their lack of activity at levels prescribed for the prevention of cardiovascular disease and by their dose-limiting toxicities at high doses. The dysregulated and elevated HMG CoA reductase activity in tumors retains sensitivity to the isoprenoid-mediated posttranscriptional down-regulation, an action that complements the statin-mediated inhibition and may lead to synergistic impact of blends of isoprenoids and lovastatin on tumor HMG CoA reductase activity and consequently tumor growth. d-gamma- and d-delta-tocotrienols, vitamin E isomers containing an isoprenoid moiety, and lovastatin-induced concentration-dependent inhibition of the 48-hr proliferation of murine B16 melanoma cells with IC50 values of 20 +/- 3, 14 +/- 3, and 1.5 +/- 0.4 microM respectively. A blend of lovastatin (1 microM) and d-gamma-tocotrienol (5 microM) totally blocked cell growth, an impact far exceeding the sum of inhibitions induced by lovastatin (12%) and d-gamma-tocotrienol (8%) individually. Synergistic impact of these two agents was also shown in human DU145 prostate carcinoma and human A549 lung carcinoma cells. C57BL6 mice were fed diets supplemented with 12.5 mg lovastatin/kg body weight, 62.5 mg d-delta-tocotrienol/kg body weight, or a blend of both agents for 22 days following B16 cell implantation; only the latter had significantly lower tumor weight than those with no supplementation. Co-administration of isoprenoids that posttranscriptionally down-regulate tumor reductase may lower the effective dose of statins and offer a novel approach to cancer chemo-prevention and/or therapy.

Prenylation Inhibitors as Potential Therapeutic Drugs in Hodgkin Lymphoma.

Although the therapy of Hodgkin lymphoma has improved, patients still suffer from late toxicities and insufficient treatment of relapses. Hence, new treatment strategies are needed. Statins are used to treat hypercholesterolaemia and prevent cardiovascular disease. There is evidence for a preventive effect of statins in cancer, including lymphoma. So far, nothing is known about a therapeutic activity of statins or related drugs in Hodgkin lymphoma. Statins block the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to downstream isoprenoid products like farnesyl and geranylgeranyl-pyrophosphate, inhibiting protein prenylation and leading to apoptosis in several malignancies. The anti-tumour activity of the statin simvastatin and three specific prenylation inhibitors (FTI-277, GGTI-298 and tipifarnib) in Hodgkin lymphoma cells was evaluated in cytotoxicity and apoptosis assays. Furthermore, simvastatin was tested in a xenograft model for human Hodgkin lymphoma. First simvastatin induced caspase-related apoptosis in Hodgkin lymphoma cells via the isoprenoid pathway. The IC50 of simvastatin in cytotoxicity assays was < 2 μM. Second simvastatin showed high activity in a mouse model for Hodgkin lymphoma, delaying tumour establishment and inhibiting tumour growth. Finally the geranylgeranyltransferase inhibitor GGTI-298 and the farnesyltransferase inhibitors FTI-277 and tipifarnib displayed anti-tumour activity in Hodgkin lymphoma cells (approximate IC50 in cytotoxicity assays: 20, 7.5 and < 0.1 μM respectively). Importantly, the concentration of simvastatin that induced apoptosis in Hodgkin lymphoma cells was in the range of 2 μM. This corresponds to plasma levels reached in humans in clinical trials with high dose statins in cancer. Thus, our results suggest two possible applications of simvastatin in Hodgkin lymphoma: First simvastatin in high doses could be included in polychemotherapy regimens to improve the remission rate of relapsed patients. Second simvastatin in the cholesterol-lowering dose should be evaluated as a preventive drug for patients in remission to avoid relapses. Moreover, in comparison to other haematological malignancies, the farnesyltransferase-inhibitor tipifarnib was highly cytotoxic in Hodgkin lymphoma cells. Given its activity in clinical trials in haematological neoplasia, its clinical evaluation in Hodgkin lymphoma is warranted. Taken together, prenylation inhibitors are promising drugs for the treatment of Hodgkin lymphoma.