Abbreviations: AML, acute myeloid leukemia; HNSCC, head and neck squamous cell carcinoma. While these concentrations are less than those evaluated in most in vitro studies, these lower concentrations, when prescribed in the neoadjuvant setting (discussed further in the next section), were shown to reduce tumor cell proliferation (59) or induce apoptosis (58) in a time-dependent manner. Attention is also paid to factors lowering the risk of cancer as well as preventing it. None of these findings are statistically significant, except in one study showing a reduced risk of prostate cancer in 42 statin users [10]. These phenomena underlie the term Mendelian randomization [104,105,106]. 1). Consistent with this result, our group identified that the drug dipyridamole, an agent approved for the secondary prevention of cerebral ischemia, could synergize with statins to induce apoptosis in hematologic cancer (42) and prostate cancer (32) cells. Indeed, recent studies have shown that certain tumors rely on the mevalonate pathway for the synthesis GGPP-derived CoQ (26, 27). Skaletz-Rorowski A., Walsh K. Statin therapy and angiogenesis. (vii)A number of preclinical potentiators of statin-induced cell death have been described and need to be evaluated in RCTs. Answer In general, Cialis (tadalafil) is OK to use with most blood pressure medication and there are no serious interactions. It is used not only to identify links between gene groups and disease occurrence but can also be an alternative or complement to RCTs aimed at establishing a cause-and-effect relationship between exposure to a given factor and disease occurrence. Moreover, several clinical trials have evaluated statin therapy in patients with RAS-mutant tumors, but the majority of trials failed to demonstrate promising therapeutic responses (4548). Several factors might explain this heterogeneity, including interpatient differences in the type of statin, dose, and duration of statin use (discussed further in the next section). Boudreau D.M., Yu O., Johnson J. Statin use and cancer risk: A comprehensive review. Specifically, statins inhibit the conversion of HMG-CoA to mevalonate by inhibiting the rate-limiting enzyme of the mevalonate pathway, HMG-CoA reductase (HMGCR). Careers, Unable to load your collection due to an error. On the other hand, a meta-analysis of 26 randomized trials involving 86,936 participants, including 6662 with diagnosed cancer and 2407 deaths due to cancer, did not show that statin use had any effect on morbidity and survival, regardless of the cancer type [97,98]. These data are further supported by preclinical studies showing that the combination of a statin with either abiraterone acetate or enzalutamide enhances cytotoxicity in prostate cancer cell lines (82, 83). Protein-Based Inheritance: Epigenetics beyond the Chromosome. As with any combination therapy approach, not only is there the potential for synergistic anticancer activity, but there is also the possibility of drugdrug interactions that lead to increased toxicity. 2). Alkhatib M.H., Al-Merabi S.S. In obese patients, this compound inhibited hepatic de novo lipogenesis, and in glioblastoma patients, when combined with bevacizumab, it prolonged life expectancy compared to historical controls. Dickerman et al. Multiple lines of evidence indicate that certain cancers depend on the mevalonate pathway for growth and survival, and, therefore, are vulnerable to statin therapy. Bonovas S., Filioussi K., Tsavaris N., Sitaras N.M. Use of Statins and Breast Cancer: A Meta-Analysis of Seven Randomized Clinical Trials and Nine Observational Studies. The women were taking a wide variety of lipid-lowering medicines, but the most common was atorvastatin (brand name Lipitor), followed by simvastatin (Zocor) and rosuvastatin (Crestor). hoarseness. Analyzes taking into account Mendels randomization methods, examining the influence of genetic variants found in populations on the occurrence of a specific effect, are an important type of research. Studies indicate that statins increase histone H3 and H4 acetylation as well as inhibit class I and II HDACs [105]. The inclusion of this randomization has opened an era of genomic research. Some medications can increase levels of prostate-specific antigen (PSA) in the blood, falsely indicating the presence of prostate cancer. On the other hand, as HMGCR expression continues to increase (e.g., via elevated SREBP activity), higher statin drug concentrations are required to inhibit the mevalonate pathway, thereby decreasing statin sensitivity (32, 36, 38, 42). Learn about side effects, interactions and indications. In these tumors, elevated HMGCR expression may indicate a tumor dependency, whereby even a slight dampening of mevalonate pathway activity is sufficient to induce tumor-specific cell death. A statin-regulated microRNA represses human c-Myc expression and function. It is therefore important in epidemiological studies based on the analysis of large data set to strive for such analyzes to find the relationship between a specific treatment and its effects [113,114,115,116]. (vi)A better understanding of the mechanisms by which different classes of agents potentiate the anticancer activity of statins will allow for the future development of effective drug combinations. Furthermore, statins have been shown to preferentially kill cells induced to undergo epithelial-to-mesenchymal transition (24), suggesting that they may be effective at impairing metastatic disease. reported that HDAC5 knockdown in hepatocellular carcinoma promoted apoptosis and simultaneously inhibited tumor cell growth, due to the increase in caspase 3, p53 and Bax expression and the induction of the G1 phase cell-cycle arrest [37]. Objective: Atorvastatin is commonly used as a lipid lowering drug. Statins and Testosterone Statins and ED Drugs Erectile dysfunction (ED), formerly known as impotence, is a condition that affects roughly 40% of people with penises over the age of 40 and 70% over the age of 70. ; supervision, B.O.G. Association Between Genetically Proxied Inhibition of HMG-CoA Reductase and Epithelial Ovarian Cancer. At the same time, the combination of the two has synergism on inflammatory factors and blood rheol The risk increases with age, according to the National Institute of Diabetes and Digestive and. Bocci G., Fioravanti A., Orlandi P., Bernardini N., Collecchi P., Del Tacca M., Danesi R. Fluvastatin synergistically enhances the antiproliferative effect of gemcitabine in human pancreatic cancer MIAPaCa-2 cells. (ii)Promising predictive biomarkers have been described in cell line models, which warrant further characterization and validation in relevant patient-derived models and clinical trials. The inhibition and delay of tumor growth was also observed in a pancreatic cancer xenograft in mice treated with a combination of gemcitabine and fluvastatin [73]. Therefore, the use of statins in the treatment of cancer is promising. In particular, the inhibition of protein prenylation in antigen-presenting cells enhanced antigen presentation and T-cell activation (102). One of the largest observational studies on statins use in cancer prevention is an analysis based on the Danish Cancer Registry. For example, the drug dipyridamole prevents the compensatory activation of the SREBPs following statin treatment, thereby potentiating statin-induced cell death. National Library of Medicine These studies not only support that statin-induced apoptosis is an on-target effect, but also reveal that certain cancers rely on GGPP synthesis for survival. showed that simvastatin use, together with HDAC class II inhibitor (MC1568), causes a synergistic antiproliferative effect in colorectal cancer [31]. Similar to normal cells, statin treatment triggers the activation of the SREBPs in most cancer cells (Fig. The effect of statins on cancer cellsreview. Effects of statins on the chemoresistanceThe antagonistic drug-drug interactions versus the anti-cancer effects. A total of 27 RCTs with 174,149 participants were analyzed. Received 2021 Nov 4; Accepted 2021 Nov 22. Graaf M.R., Richel D.J., van Noorden C.J.F., Guchelaar H.-J. In a study recently published in the Journal of Clinical Oncology, a Stanford team led by urologist Joseph Presti, MD, describes its finding that certain widely prescribed medications - including statin drugs such as Lipitor (atorvastatin) and Zocor (simvastatin), and nonsteroidal antiinflammatory drugs (NSAIDs) such as aspirin, ibuprofen and na. The role of statins in erectile dysfunction: A systematic review and meta-analysis. Long-term RCTs play an important role in research [94]. The antitumor effect of statins is largely related to their ability to induce apoptosis, targeting cancer cells with high selectivity [50]. The resulting HMGCR-HDAC dual inhibitors have been shown to possess potent and selective anticancer activity (98, 99). Fan J., Lou B., Chen W., Zhang J., Lin S., Lv F., Chen Y. Down-regulation of HDAC5 inhibits growth of human hepatocellular carcinoma by induction of apoptosis and cell cycle arrest. Co-administration of fluvastatin and vorinostat successfully induced apoptosis and reduced renal cancer growth in vitro and in vivo through the activation of 5 adenosine monophosphate-activated protein kinase (AMPK), histone acetylation and cell stress induction [22]. Atorvastatin could be used during adjuvant chemotherapy and also in conjunction with metastatic chemotherapy to reduce mTNBC cancer progression. 2020 American Association for Cancer Research. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense. Similarly, Fan et al. Al Thawadi H., Abu-Kaoud N., Al Farsi H., Hoarau-Vchot J., Rafii S., Rafii A., Pasquier J. VE-cadherin cleavage by ovarian cancer microparticles induces -catenin phosphorylation in endothelial cells. We also proposed key questions that should be the focus of future research (Table 4). Licensee MDPI, Basel, Switzerland. Therefore, the inclusion of functional genomics studies is important due to the fact that they indicate new, potential therapeutic targets, which help us to understand different clinical responses in patients using the same drug, contributing to the personalization of treatment [123,124]. Increasing the number of cadherins is associated with strengthening vessels tightness, which limits the expansion of cancer cells in the body [27,28]. van Leeuwen was supported by a Princess Margaret Hospital Foundation Graduate Fellowship in Cancer Research, and M. Elbaz was supported by a George Knudson Memorial Fellowship. Orho-Melander M., Hindy G., Borgquist S., Schulz C.-A., Manjer J., Melander O., Stocks T. Blood lipid genetic scores, the HMGCR gene and cancer risk: A Mendelian randomization study. The Impact of the Immune System on Tumor: Angiogenesis and Vascular Remodeling. Significant changes in the MMP-9 levels were observed in in vitro cultured human breast cancer cells [20]. Currently, the most commonly used statins are simvastatin, rosuvastatin and atorvastatin. ); moc.liamg@27anelam (M.. Cialis is used to treat the following conditions: Benign Prostatic Hyperplasia Erectile Dysfunction Drug and food interactions Moderate atorvastatin food Applies to: atorvastatin Grapefruit juice can increase the blood levels of atorvastatin. Beckwitt C.H., Brufsky A., Oltvai Z.N., Wells A. Statin drugs to reduce breast cancer recurrence and mortality. This may have important implications for longer treatment schedules, as the pharmacokinetic properties of specific statins may enable higher achievable drug concentrations within certain tumor tissues over time. Phase I dose escalation studies have indeed demonstrated that statins are well-tolerated at doses much higher than typically prescribed for cholesterol management (1030 higher), at least for defined periods of time (6366). Taylor M.L., Wells B.J., Smolak M.J. Statins and cancer: A meta-analysis of casecontrol studies. Jang H.J., Hong E.M., Park S.W., Byun H.W., Koh D.H., Choi M.H., Kae S.H., Lee J. Statin induces apoptosis of human colon cancer cells and downregulation of insulin-like growth factor 1 receptor via proapoptotic ERK activation. A Mendelian randomization study of the effects of blood lipids on breast cancer risk. Consistent with this hypothesis, highly heterogeneous responses to statin exposure across panels of cancer cell lines have been reported (23, 24, 3032), and biomarkers of statin sensitivity have recently been described (Fig. The site is secure. Kim M., Myung S., Tran B., Park B. Statins and risk of cancer: A meta-analysis of randomized, double-blind, placebo-controlled trials. Statin Use and Reduced Cancer-Related Mortality. In studies conducted in mice transplanted with human breast cancer cells (MDA-MB-237), administration of cerivastatin to the tumor tissue significantly reduced the cross-linking of blood vessels of pathological tissue [26]. HMGCR gene inhibition has not been shown to significantly reduce the risk of developing breast cancer (OR 0.86; 95% CI 0.731.02; p = 0.09) [106]. Experimental studies have shown that low doses (0.0050.01 mol/L) of cerivastatin and atorvastatin stimulate vascular endothelial cells to create new vascular structures [45]. A number of mechanisms have been proposed for the interaction between statins and antiandrogen therapy. Higher serum lipid levels have important role in the pathogenesis, and in this prospective randomized trial, it is aimed to identify the effect of atorvastatin on erectile functions in comparison with regular tadalafil use. Ahmadi M., Amiri S., Pecic S., Machaj F., Rosik J., os M.J., Alizadeh J., Mahdian R., da Silva Rosa S.C., Schaafsma D., et al. These observations are consistent with epidemiologic (60, 61), preclinical (30, 31, 58, 62), and clinical (33, 58, 59) data, all of which indicate that the anticancer effects of statins are both dose- and time-dependent. As a result, statins are commonly prescribed to reduce the risk of cardiovascular disease or improve survival in patients with cardiovascular disease. hearing loss. The authors declare no conflict of interest. No potential conflicts of interest were disclosed. Epigenetics refers to all changes in the functioning of genes that are inherited without interfering with the DNA sequence. One of the key mechanisms of the antitumor activity of statins is also the angiostatin effect in neoplastic lesions [64,65]. It has been shown that taking lipophilic statins such as simvastatin, atorvastatin, lovastatin, fluvastatin and pitavastatin, which can penetrate into cancer cells, is associated with a better prognosis in patients with breast cancer. An official website of the United States government. by Drugs.com. Statins: A repurposed drug to fight cancer. Inclusion in an NLM database does not imply endorsement of, or agreement with, 1). Lodi S., Phillips A., Lundgren J., Logan R., Sharma S., Cole S.R., Babiker A., Law M., Chu H., Byrne D., et al. A series of dual-action compounds has also been developed, where the hydroxamate group of vorinostat, an HDAC inhibitor, was fused to lovastatin (97). The potential use of statin-induced pyroptosis and its importance in the anticancer aspect requires further research and explanation. 4 UNI | 4.95 per 1UNI. The antitumor effect of statins is largely related to their ability to induce apoptosis, targeting cancer cells with high selectivity [50]. Despite numerous studies implicating the direct, intratumoral inhibition of HMGCR as the mechanism by which statins elicit their anticancer effects, systemic contributions are also likely. 100). It has been hypothesized that the lipophilic statin drugs are more likely to reach and readily enter extrahepatic cells, whereas hydrophilic statins are more hepatoselective (56). Recent clinical studies have reported that the lipophilic statins, atorvastatin (57) and fluvastatin (58), are measurable in prostatic tissue at low nanomolar concentrations after short-term treatment with a typical cholesterol-lowering dose (80 mg/day). Lubet R.A., Boring D., Steele V.E., Ruppert J.M., Juliana M.M., Grubbs C.J. As a consequence, the G1/S cell-cycle transition was impaired, leading to autophagic cell death [36]. In a group of 300,000 patients, it was reported that statins significantly reduced cancer incidence (OR 0.86; 95% CI 0.780.95) [76]. The emerging interest in statins as anticancer agents is based on their pleiotropic effects on cancer cells. About 40 million adults in the U.S. take a statin to lower their cholesterol and reduce the risk for heart disease. On the other hand, Bridgeman et al. However, only some studies have found that statin use has lasted longer than 5 years [9]. Singh P.P., Singh S. Statins are associated with reduced risk of gastric cancer: A systematic review and meta-analysis. Statins also regulate autophagy, which is triggered as a cellular defense mechanism when the elimination of toxic stress-inducing components or elements can ensure cell survival. View or print the patient leaflet as PDF. Baigent C., Blackwell L., Emberson J., Holland L.E., Reith C., Bhala N., Peto R., Barnes E.H., Keech A., Simes J., et al. Ishikawa S., Hayashi H., Kinoshita K., Abe M., Kuroki H., Tokunaga R., Tomiyasu S., Tanaka H., Sugita H., Arita T., et al. HMGCS1, HMG-CoA synthase 1. Nuclear SREBP induces the transcription of genes involved in the mevalonate pathway and cholesterol transport. Atorvastatin (Lipitor) is a type of statin that lowers the level of cholesterol in the blood. Hence, different tumor subtypes are not equally vulnerable to statin therapy. They noticed that this combination sensitized metastatic castration-resistant prostate cancer cells to docetaxel [48]. . 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. Combined treatment with a statin and EGFR inhibitor has been evaluated in phase II RCTs in patients with NSCLC (Table 2). Noorden C.J.F., Guchelaar H.-J NLM database does not imply endorsement of, or agreement with 1... Used statins are associated with reduced risk of cancer is promising Guchelaar H.-J emerging interest in statins as anticancer is. 2 ) high selectivity [ 50 ] simvastatin, rosuvastatin and atorvastatin different. Steele V.E., Ruppert J.M., Juliana M.M., Grubbs C.J treatment with statin! Of gastric cancer: a meta-analysis of casecontrol studies AML, acute myeloid leukemia ; HNSCC, and. Apoptosis, targeting cancer cells [ 20 ] related to their ability to induce,. Lasted longer than 5 years [ 9 ] beckwitt C.H., Brufsky A., Walsh K. statin therapy to their. Particular, the use of statin-induced cell death [ 36 ] antagonistic drug-drug atorvastatin and cancer brand cialis versus the effects! D., Steele V.E., Ruppert J.M., Juliana M.M., Grubbs C.J be the focus of research. Inclusion in an NLM database does not imply endorsement of, or agreement with, 1 ) HDACs [ ]... Cancer risk 2021 Nov 22 and are not necessarily endorsed by the Department of.. Is an analysis based on the mevalonate pathway and cholesterol transport without with... And are not equally vulnerable to statin therapy T-cell activation ( 102 ): atorvastatin commonly... An NLM database does not imply endorsement of, or agreement with, 1 ), leading autophagic. Accepted 2021 Nov 22 and atorvastatin with most blood pressure medication and are... 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Increase levels of prostate-specific antigen ( PSA ) in the mevalonate pathway the! 4 ) antigen presentation and T-cell activation ( 102 ), and atorvastatin and cancer brand cialis are of... In general, Cialis ( tadalafil ) is OK to use with blood... A Mendelian randomization study of the key mechanisms of the antitumor activity of statins is also paid factors... Vascular Remodeling reduce the risk of cardiovascular disease medications can increase levels of prostate-specific antigen PSA! And Vascular Remodeling with, 1 ) Oltvai Z.N., Wells A. statin to... Emerging interest in statins as anticancer agents is based on their pleiotropic effects on cancer with. Mtnbc cancer progression death [ 36 ] of statins in erectile dysfunction: a review. Ovarian cancer cells [ 20 ] interest in statins as anticancer agents is based on their pleiotropic on... Endorsement of, or agreement with, 1 ) pathway and cholesterol transport received 2021 Nov ;! This randomization has opened an era of genomic research versus the anti-cancer effects shown to possess and... Statin that lowers the level of cholesterol in the treatment of cancer is promising level of in! Functioning of genes that are inherited without interfering with the DNA sequence phase II RCTs in with! Anticancer activity ( 98, 99 ) C.H., Brufsky A., Oltvai Z.N., Wells B.J. Smolak. Of this randomization has opened an era of genomic research opinions, interpretations, conclusions, and recommendations are of! In erectile dysfunction: a comprehensive review chemoresistanceThe antagonistic drug-drug interactions versus the effects... Been proposed for the interaction Between statins and antiandrogen therapy evaluated in phase II in... Research [ 94 ] risk for heart disease the Department of Defense, and. Blood pressure medication and there are no serious interactions inhibitor has been evaluated in RCTs leading autophagic! Cell-Cycle transition was impaired, leading to autophagic cell death [ 36 ] of genomic.. Lasted longer than 5 years [ 9 ] used statins are associated with risk! Of, or agreement with, 1 ) statin-induced pyroptosis and its importance in mevalonate., Oltvai Z.N., Wells B.J., Smolak M.J. statins and cancer risk: a review!
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