Statins in oncological research: from experimental studies to clinical practice.

Critical Reviews in Oncology/Hematology 92 (2014) 296–311

Statins in oncological research: From experimental studies to clinical practice Peter Kubatka a, Peter Kruzliak b,∗, Vladimir Rotrekl c, Sarka Jelinkova c, Beata Mladosievicova d b c

a Department of Medical Biology, Jessenius Faculty of Medicine in Martin, Comenius University, Bratislava, Slovak Republic Department of Cardiovascular Diseases, International Clinical Research Centre, St. Anne’s University Hospital and Masaryk University, Brno, Czech Republic Department of Biology, Medical Faculty, Masaryk University and International Clinical Research Centre, St. Anne’s University Hospital, Brno, Czech Republic d Institute of Clinical Pathophysiology, Faculty of Medicine, Comenius University, Bratislava, Slovak Republic

Accepted 7 August 2014

Contents 1. 2.

3. 4. 5.

6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Statins in oncological research: evaluation of anti-tumor effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Inhibition of proliferation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Induction of apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Impact on angiogenesis and metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Statin effect on stem cells and cancer stem cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Statins and cancer risk in animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Statins in rat breast carcinoma model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Statin use, cancer risk and cancer-related mortality in clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Statins and their potential clinical implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Esophageal cancer, Barrett’s esophagus and statins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Hepatocellular carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Colorectal cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Statins’ unintended effects and hepatotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions and future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract Statins, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors are commonly used drugs in the treatment of dyslipidemias, primarily raised cholesterol. Recently, many epidemiological and preclinical studies pointed to anti-tumor properties of statins, including anti-proliferative activities, apoptosis, decreased angiogenesis and metastasis. These processes play an important role in carcinogenesis and, therefore, the role of statins in cancer disease is being seriously discussed among oncologists. Anti-neoplastic properties of statins combined with an acceptable toxicity profile in the majority of individuals support their further development as anti-tumor drugs.

∗ Corresponding author at: Department of Cardiovascular Diseases, International Clinical Research Centre, St. Anne’s University Hospital and Masaryk University, Pekarska 53, 656 91 Brno, Czech Republic. Tel.: +420 608 352 569; fax: +420 543 181 111. E-mail addresses: [email protected], [email protected] (P. Kruzliak).

http://dx.doi.org/10.1016/j.critrevonc.2014.08.002 1040-8428/© 2014 Elsevier Ireland Ltd. All rights reserved.

P. Kubatka et al. / Critical Reviews in Oncology/Hematology 92 (2014) 296–311

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The mechanism of action, current preclinical studies and clinical efficacy of statins are reviewed in this paper. Moreover, promising results have been reported regarding the statins’ efficacy in some cancer types, especially in esophageal and colorectal cancers, and hepatocellular carcinoma. Statins’ hepatotoxicity has traditionally represented an obstacle to the prescription of this class of drugs and this issue is also discussed in this review. © 2014 Elsevier Ireland Ltd. All rights reserved.

Keywords: Statins; Anti-tumor properties; Carcinogenesis; Cancer therapy; Cancer risk reduction; Chemoprevention

1. Introduction A class of cholesterol-lowering drugs, 3-hydroxy3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, have gained a great deal of attention because of their pleiotropic effects, which may be beneficial in various vascular diseases. The discovery of statins significantly changed the approach in dyslipidemic therapy and tremendously decreased morbidity and mortality from cardiovascular events. Statins had become a first choice in current prescribing practice and are pivotal in the primary and secondary prevention of cardiovascular disease (CVD) [1–4]. Recent findings unequivocally support statins for primary prevention in CVD. Taylor et al. [5] assessed the effects, both harms and benefits, of statins in people with no history of CVD. Eighteen randomized control trials were included (56,934 participants). Fourteen trials recruited patients with specific conditions (hyperlipidemia, diabetes, hypertension, microalbuminuria). Reductions in all-cause mortality, major vascular events and revascularisations were found with no excess of adverse events among people treated with statins. Recently, much debate has focused on the use of statins for primary prevention in relation to drug safety due to worsened hyperglycemia. Data from the Cholesterol Treatment Trialists’ Collaborators demonstrated a 9% reduction in all-cause mortality and a 25% reduction in major vascular events even among low-risk patients. A 2013 Cochrane review corroborated these findings including a 14% reduction in all-cause mortality and a 25% reduction in cardiovascular disease events with statin therapy despite an 18% increase in incident diabetes. Statins effectively lowered atherogenic lipoproteins and resulted in clinically significant reductions in cardiovascular morbidity and mortality [6]. Statins are generally well-tolerated drugs and this was one of the reasons why they replaced previously used drugs in the treatment and prevention of cardiovascular events. The pleiotropic effects of statins include improvement of endothelial dysfunction, increased nitric oxide bioavailability, antioxidant effects, anti-inflammatory properties, inhibition of cardiac hypertrophy, stabilization of atherosclerotic plaques, and inhibition of atherosclerotic process, thereby yielding potential benefits for patients at risk of cardiovascular disease, regardless of cholesterol levels [1–4]. Beyond cholesterol-reducing properties, statins exhibit many other biological activities which are responsible for

their beneficial effects in organisms. As an essential step in biosynthesis of the mevalonate pathway statins affect the levels of cholesterol and also other downstream products (isoprenoids) which are important in key physiologic processes such as cell signaling, translation, post-translational modifications, proliferation, apoptosis, and differentiation [7,8]. These processes play an important role in carcinogenesis and, therefore, the anti-tumor properties of statins are intensively evaluated by investigators. The mechanism of action, in vitro and in vivo anti-neoplastic properties of statins, their use in cancer therapy and prevention, and possible adverse effects in cancer patients are the main topics of this review.

2. Statins in oncological research: evaluation of anti-tumor effects Numerous in vitro experiments showed that statins demonstrate significant tumor-suppressive effects against various leukemia and solid tumor cells. The several conclusions were drawn from experimental studies. Firstly, different statins have apparent anti-proliferative and proapoptotic effects on various cancer cell lines. Secondly, the anti-neoplastic effects demonstrated only lipophilic statins. Fluvastatin, simvastatin, and lovastatin were cytotoxic against breast adenocarcinoma cells [7]; atorvastatin, simvastatin, lovastatin, and cerivastatin were cytotoxic against myeloma cancer cells [8] and simvastatin and lovastatin against ovarian cancer cells [9]. Thirdly, statins differ in their anti-neoplastic potential. Four acute myeloid leukemia cell lines using different statins were evaluated. Cell lines were most sensitive to cerivastatin, ten-fold less sensitive to lovastatin and fluvastatin, and only weakly sensitive to atorvastatin [10]. The observed differences in anti-neoplastic effects are explained by their different physicochemical characteristics (lipophilicity of statins is reflected to their potential to cross the cell membrane) and by their differential activation of specific receptors, such as for example nuclear pregnane Xreceptor, farnesoid X-receptor and constitutive androstane receptor [11]. Fourthly, statin cytotoxicity may depend on the target tumor type. Dimitroulakos et al. have identified a subset of tumors (juvenile monomyelocytic leukemia, medulloblastoma, rhabdomyosarcoma, choriocarcinoma, and squamous cell carcinomas of the cervix, head and neck) that are sensitive to lovastatin-induced apoptosis and show HMG-CoA reductase as a potential therapeutic target of these cancers [12].

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And finally, statins modify normal fibroblast, endothelial, and smooth muscle cell proliferation [13]. However, normal cells appear to be more resistant to the anti-proliferative effects of statins relative to cancer cells, which are much more likely to proliferate [12]. The mevalonate pathway produces various end products that are important for cellular functions. One of them, cholesterol, can mask the cancer stem cell associated glycosphingolipid antigens and decrease their immunoreactivity [14]. The effect of statins leads to reduced levels of mevalonate and its downstream products which play important roles in physiological processes such as cell signaling, protein synthesis, post-translational modifications, cell growth, and differentiation [15]. Mevalonate is a precursor of dolichol, geranyl pyrophosphate (GPP), and farnesyl pyrophosphate (FPP) that regulate the cell cycle. Dolichol stimulates DNA synthesis and is linked to many cancer cell proteins. GPP and FPP induce isoprenylation of the intracellular Gproteins (Ras, Rho) which regulates the signal transduction in membrane receptors involved in processes of cell proliferation, differentiation, and apoptosis. There is emerging evidence that the above-mentioned activities result in statins’ anti-proliferative, proapoptotic, anti-angiogenetic, and antiinvasive effects, as addition of geranylgeraniol a product of statin-inhibited mevalonate synthesis pathway can overcome the statin induced effect such as for example lovastatin induced proliferation block in C6 glioma cell [16]. These processes are crucial for oncogenesis and therefore are seriously evaluated in experimental cancer research. Fig. 1 summarizes the mechanism of action of statins on cancer cells. 2.1. Inhibition of proliferation About 20 years ago, it was already suggested that statins could inhibit tumor cell growth and possibly prevent carcinogenesis [17]. Statins inhibit proliferation of cancer cells in vitro, either in vivo by inhibition of HMG-CoA reductase and subsequently through a decrease of isoprenoids levels. In vitro studies on various cell lines have shown that statins synchronize tumor cells by blocking G1/S [18,19] and G2/M transition [20,21] in the cell cycle. Ras and Rho gene mutations are found in a variety of pancreas, thyroid, colon, myeloid leukemia, and lung cancer types. The inhibition of Ras farnesylation by lovastatin was associated with a reduction of proliferation and migration in human glioblastoma cells [22]. In another study, cerivastatin has been demonstrated to inhibit Ras- and Rho-mediated cell growth [23]. On the other hand, the inhibition of cell proliferation by statins may be also independent of Ras function [24]. It has been found that the anti-proliferative effects of statins are the consequence of p21 and p27 (cyclin-dependent kinase inhibitors) stabilization [23]. In the same study of DeNoyelle et al., cerivastatin-induced G1-arrest in breast cancer cells without the signs of apoptosis [23]. These data suggest that statin-induced proliferation is independent from statininduced apoptosis. These findings have led researchers to

hypothesize that statins might manifest anti-neoplastic effects in a variety of cancer cell lines. Several studies demonstrated anti-proliferative effects of statins in animal cancer models. In rat mammary carcinogenesis, the expression decrease of proliferation marker Ki67 by 27% in tumor cells from animals treated with simvastatin compared to control cells were observed [25]. In rats, simvastatin (after local application) apparently reduced the growth of gliomas [13]. Pravastatin significantly decreased the incidence of tumors in rat colon carcinogenesis [26]. Furthermore, lovastatin was effective in mice neuroblastoma [27] and rat liver cancer model [28]. The above-mentioned data from in vitro and in vivo experiments indicate that statins inhibit proliferation in various tumor types. 2.2. Induction of apoptosis The mechanism of statin-induced apoptosis appears to be mediated predominantly via the depletion of geranylgeranylated proteins. In human acute myeloid leukemia (AML) cells, apoptosis induced by lovastatin was abrogated by mevalonate and GPP and partially reversed by FPP. Other products of mevalonate pathway did not affect lovastatininduced apoptosis in AML cell lines [29]. Generally, higher proapoptotic activity have shown lipophilic statins compared to hydrophilic [9]. Recently a potential mechanism for statin related depletion of mevalonate pathway product-modified proteins and its proapoptotic effect was described as statin mediated-disrupted binding of RhoA inhibitor GDI␣ and subsequent increase in the GTP-bound forms of RhoA, Rac1 and Cdc42. While Rac1 and Cdc42 may affect also the cell cycle of statin treated cells all three proteins induce apoptosis either by suppression of antiapoptotic proteins such as Bcl2, or activation of superoxide-activated JNK pathway [30]. Several in vitro cancer studies have found a proapoptotic effect of statins in different cell lines. An intensive apoptotic response in cells derived from squamous cell carcinoma of the cervix, head, and neck, juvenile monomyelocytic leukemia, rhabdomyosarcoma, medulloblastoma, malignant mesothelioma, and astrocytoma after lovastatin treatment was observed [12,22,30]. Different statins were not equipotent in apoptosis induction. In AML cells, cerivastatin was at least 10 times more potent than other statins in inducing apoptosis. On the other hand, leukemic cells from patients with AML were weakly responsive to lovastatin [10]. Cancer cells themselves significantly differ in their sensitivity to statin-induced programmed cell death. Neuroblastoma and AML cells are more sensitive compared to lymphoblastic leukemia cells [31,32]. Although they are not the primary target, statins seem to be capable of activation of caspases; some of them are considered as “execution” proteins of apoptosis. Cafforio et al. found that cerivastatin caused the death of human myeloma cells by activating caspase-3, caspase-8, and caspase-9 [8]. Lovastatin-induced apoptosis in prostate cancer cell line through activation of caspase-7 [33] and in leukemic cells


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Fig. 1. The mechanism of action of statins on cancer cells. Black arrows mean direct mechanism of action, blue arrows represent indirect mechanism. (For interpretation of the references to color in text, the reader is referred to the web version of this article.)

by activation of caspase-3 [34]. Similarly, Shellman et al. have pointed to the fact that lovastatin enhances activity of caspase-3 50-fold in mice and the human model of melanoma [35]. Simvastatin has been shown to activate mitochondrial caspase-9 and thus induce apoptosis in chronic lymphocytic leukemia cells [36]. Finally, atorvastatin-induced apoptosis in activated hepatic stellate cells and highly increased protease activity of caspase-9 and caspase-3 [37]. In one in vivo study, fluvastatin has caused caspase-3 to increase by 8.5% in rat mammary gland cancer cells [38]. Moreover, proposed mechanisms for statin-mediated apoptosis include an upregulation of proapoptotic protein expression (Bax), combined with decreased antiapoptotic protein expression (Bcl-2) [39]. These effects have been observed in both hematologic and solid tumor cell lines and also in models in vivo. In the specimens of mammary tumors, atorvastatin profoundly decreased mRNA expression of Bcl-2 gene and slightly increased Bax mRNA expression compared to untreated tumor cells in the rat breast carcinoma model [40]. In the same model, immunohistochemical analysis has shown a significant proapoptotic shift in Bcl-2/Bax ratio in tumor cells after simvastatin treatment [25]. 2.3. Impact on angiogenesis and metastasis Neovascularisation is thought to be important for the growth of primary tumors and metastasis. Several experimental studies have shown that statins inhibit cell migration and proliferation [41,42]. Since endothelial cell migration

and proliferation are crucial steps in angiogenesis, the effects of statins on angiogenesis have been assessed. It has been reported that statins can stimulate [43] or inhibit [44] blood vessel formation depending on the cancer cell type. Cerivastatin in high doses decreased tumor vascularization by 51% in a murine Lewis lung cancer model [45]. Lovastatin increased the inhibitory effect of TNFalfa on tumor growth and vascularization in mice injected with Ras-3T3 cancer cells [46]. In contrast, statins have been shown to stimulate protein kinase B, which in turn activates endothelial nitric oxide synthase and increases angiogenesis [47]. Interestingly, a biphasic effect of atorvastatin and cerivastatin on angiogenesis in human dermal microvascular endothelial cells was observed. Low concentrations of these statins enhanced endothelial cell proliferation, whereas relatively high doses inhibited angiogenesis [45]. Statins by unknown mechanism, but demonstrably decrease the levels of one of the most important molecules of angiogenesis, vascular endothelial growth factor (VEGF), and thereby inhibit capillary formation [48]. Immunohistochemical analysis of rat mammary tumor cells has shown VEGFR-2 expression decrease by 86% after fluvastatin treatment [38]. Several lines of evidence suggest that statins impair the metastatic potential of tumor cells by inhibiting cell migration, attachment to the extracellular matrix, and invasion of the basement membrane. Different statins have been demonstrated to reduce endothelial leukocyte adhesion molecule E-selectin [49] and matrix metalloproteinase-9 expression [50]. Recently, simvastatin and lovastatin were used in

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the treatment of human breast epithelial cells with active H-Ras mutation (H-Ras MCF10A) [51]. Statins markedly decreased isoprenylated H-Ras in membrane fraction while the unprenylated H-Ras was increased in cytosol fraction, demonstrating that these drugs inhibited membrane anchoring of H-Ras in MCF10A cells. Simvastatin and lovastatin significantly inhibited H-Ras-induced invasion of MCF10A cells which was reversed by farnesyl pyrophosphate (FPP). Statins downregulated matrix metalloproteinase (MMP)-9 and to a lesser extent, MMP-2 in H-Ras MCF10A cells [51]. In another study, the effect of different statins on in vitro proliferation, migration, and invasion of melanoma cells was evaluated. Lovastatin, mevastatin and simvastatin inhibited the growth, cell migration and invasion of HT144, M14, and SK-MEL-28 melanoma cells [52]. Brown et al. focused on the mechanism by which statins reduce prostate cancer progression. They have found that lipophilic statins reduce the migration and colony formation of PC-3 cells in human bone marrow stroma by inhibiting geranylgeranyl pyrophosphate (GGPP) production, reducing the formation and the spread of metastatic prostate colonies [53]. Another study investigated the effect of simvastatin on human endometrial stromal (HES) cell invasiveness and the expression of selected genes relevant to invasiveness. Simvastatin induced a concentration-dependent reduction of invasiveness of HES cells. This effect of simvastatin was abrogated by GGPP but not by FPP. Simvastatin also reduced the mRNA levels of MMP2, MMP3, and CD44, but increased TIMP2 mRNA; all these effects of simvastatin were partly or entirely reversed in the presence of GGPP [54]. Statins have been shown to inhibit epithelial growth factor (EGF)-induced tumor cell invasion. Treatment of pancreatic cancer cells with fluvastatin markedly attenuated EGF-induced translocation of RhoA from the cytosol to the membrane fraction and actin stress fiber assembly, whereas it did not inhibit the tyrosine phosphorylation of EGF receptor and c-erbB-2. HMG-CoA reductase inhibitors affect RhoA activation by preventing geranylgeranylation, which results in inhibition of EGF-induced invasiveness of human pancreatic cancer cells [55]. On the other hand, not all studies have found that statins reduce tumor metastases. Lovastatin failed to inhibit glioblastoma and colon cancer cell migration and invasion [56]. 2.4. Statin effect on stem cells and cancer stem cells Statins were found to promote proliferation of various stem cell types, including promoting endothelial progenitor cells’ proliferation via inhibiting cell cycle inhibitor p27Kip1 [57]. Interestingly statins were found to selectively slow proliferation in cancer stem cells and embryonic stem cells (hESC) compared to other cell types [58]. Recent reports suggest that the effect is connected with the selective ability of statins to affect preferentially cells with abnormal karyotype. The demonstrated presence of hESC with abnormal karyotype in prolonged culture [59] might explain the results of Lee et al. Statin treatment in such cell population seems to

selectively slow proliferation in abnormal stem cells while no proliferation effect was found in cells with normal karyotype. The mildest effect was found in case of pravastatin, while the effect of lovastatin and mevastatin was strongest [60]. The statin targeting the two major mitogenic signaling pathways such as PI3K/AKT and Mek/Erk in stem cells and progenitors [61] corresponds also to the suppression of stemness in colorectal cancer stem cells which was reflected by their inhibited DNA methyltransferase activity [62].

3. Statins and cancer risk in animal studies The first connection between statin use and cancer risk in animal studies was observed in the laboratory of MacDonald et al. The authors have found that lovastatin administration at high doses was associated with a higher incidence of hepatocellular and pulmonary cancers [63]. Similarly, the administration of simvastatin induced thyroid hypertrophy and follicular adenomas in rats [64]. However, statin-associated carcinogenicity in these studies was limited to dosages much higher than that used in clinical practice. On the other hand, there are animal studies with statins, where no carcinogenic or anti-carcinogenic activities, respectively, were found. Administration of lower lovastatin doses to dogs, rats, and monkeys was not accompanied with the changes in tumor incidence. In another study, pravastatin suppressed hepatocarcinogenesis in male Sprague-Dawley rats [65]. Authors suggested that this effect might be related to pravastatin’s inhibition of p21 (Ras) isoprenylation and thus inhibition of cell proliferation and induction of apoptosis in neoplastic lesions. The administration of enzastaurin (protein kinase C inhibitor) combined with lovastatin enhanced the anti-tumor efficacy in human hepatocellular carcinoma in vivo and in vitro [66]. Furthermore, the animal model with female mice proved that pravastatin and simvastatin may prevent colon tumorigenesis [67]. In a different mice model, tumor growth of anaplastic thyroid cancer cell line xenografts was significantly reduced after lovastatin treatment [68]. Investigators found that lovastatin inhibits tumor growth at a high dosage (5 or 10 mg/kg/day), however it promotes tumor growth at a low dosage (1 mg/kg/day). Authors suspect this duality effect might be related to different levels of vascular endothelial growth factor. In the study of Huang et al. atorvastatin was ineffective in reducing polyp formation in the MIN mouse model, with no significant effect on polyp number [69]. However, atorvastatin was effective in significantly slowing the growth of HCT116 colon cancer cell xenografts in nude mice. This reduction was due to increased levels of apoptosis. In a similar model with MIN mice, pitavastatin apparently decreased the total number of polyps by dose-dependent manner [70]. mRNA expression levels of cyclooxygenase-2, IL-6, inducible nitric oxide (iNOS), MCP-1, and Pai-1 were significantly reduced in intestinal non-polyp parts by pitavastatin treatment. Moreover, oxidative stress represented by 8-nitroguanosine in the small


intestinal epithelial cells was reduced by pitavastatin [70]. Metastatic colorectal cancer patients with v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are resistant to treatment with cetuximab. In mice, treatment with cetuximab and simvastatin reduced the growth of xenograft tumors originating from KRAS mutant cells compared with cetuximab alone. This effect was assigned to modulation of v-raf murine sarcoma viral oncogene homolog (BRAF) activity and inducing apoptosis [71]. In another study in mice, the androgen-dependent LNCaP tumors (androgen-sensitive human prostate adenocarcinoma cells derived from lymph node) regressed initially in response to castration, but the tumors eventually progressed to androgen independence and started to grow [72]. Treatment with atorvastatin or celecoxib alone suppressed the regrowth of LNCaP tumors after castration. However, a combination of low doses of atorvastatin and celecoxib had a more potent effect in reducing the growth and progression of LNCaP tumors to androgen independence than a higher dose of either agent alone. These results indicate that administration of a combination of atorvastatin and celecoxib may be an effective strategy for the prevention of prostate cancer progression from androgen dependence to androgen independence. 3.1. Statins in rat breast carcinoma model Recently the group of Dr. Kubatka realized extensive oncological research with statins in mammary carcinoma model (Table 1). The main aim of this research was the evaluation of chemopreventive effects of long-term administration of different statins in a well-established model of N-methylN-nitrosourea (NMU)-induced mammary carcinogenesis in female rats. In all experiments, the chemoprevention with statin began seven days before NMU administration and lasted until the end of the experiment, about 15 weeks after carcinogen application. In this model, researchers have used four lipophilic (atorvastatin, simvastatin, fluvastatin, and pitavastatin) and two hydrophilic (rosuvastatin and pravastatin) statins. In the first experiment, atorvastatin at a dose of 100 mg/kg in the chow suppressed tumor frequency (considered as the most sensitive parameter of rat mammary carcinogenesis) by 80.5% and tumor incidence by 49.5%, and extended latency period by 14 days when compared to the control group [40]. Invasive carcinomas in the group with atorvastatin demonstrated a higher grade of differentiation compared to carcinomas in the control (untreated) group. In the specimens of mammary tumors, atorvastatin significantly decreased mRNA expression of Bcl-2 gene but non-significantly increased Bax mRNA expression compared to the control group. In the same model, simvastatin (180 mg/kg) significantly suppressed tumor frequency by 80.5% and tumor incidence by 58.5% and lengthened the latency period by 15 days compared to control animals [25]. In this experiment, the noticeable decrease of mammary tumor frequency and incidence in rats after simvastatin treatment was accompanied with antiapoptotic Blc-2

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protein decrease and proapoptotic Bax protein increase in tumor cells [25]. Chemoprevention with simvastatin beneficially shifted the rate of malignant to benign lesions in the treated group (43% vs 57%) in comparison with the untreated control group (92% vs 8%). Moreover, a histopathological analysis of malignant tumors has revealed a shift from high grade to low grade carcinomas after simvastatin treatment. In another study, fluvastatin (200 mg/kg of chow) suppressed tumor frequency by 63% and tumor incidence by 33% in comparison with the control rats [38]. Immunohistochemical analysis of tumor cells has shown VEGFR-2 expression decrease by 86% and caspase-3 increase by 8.5% after fluvastatin treatment. Dietary-administered hydrophilic rosuvastatin (250 mg/kg) decreased tumor frequency by 39%, average tumor volume by 64%, as well as lengthened the latency period by 11 days compared to controls [73]. A histopathological analysis of mammary tumors has revealed an apparent shift from poorly differentiated to well-differentiated tumors after treatment with rosuvastatin. Because rats demonstrate different pharmacokinetics and pharmacodynamics than in humans, it was necessary to use high doses of statins to prove their anti-neoplastic effects in the above-mentioned experiments. In this regard, atorvastatin, simvastatin, fluvastatin, and rosuvastatin administered at lower doses – 10, 18, 20, and 25 mg/kg of chow (derived from clinical dosages) – did not change the parameters of mammary carcinogenesis in rats. Using the same animal model, there are also two unpublished experiments of this group. Compared to previous studies, hydrophilic pravastatin has shown only a slight anti-neoplastic effect. However, pravastatin positively shifted the rate of high grade/low grade carcinomas and increased the expression of caspase-3 by 53% and caspase-7 by 46% in mammary tumor cells compared to control cells. Surprising results with lipophilic pitavastatin in rat mammary carcinogenesis were yielded – its slight neoplastic effect was observed. Moreover, there is a paper of Lubet et al. which reported about dietary-administered atorvastatin and lovastatin either as single agents or in combination with suboptimal doses of tamoxifen or rexinoid bexarotene in the prevention of NMU-induced rat mammary carcinogenesis [74]. Atorvastatin alone in this experiment in high doses of 125 and 500 mg/kg of chow did not significantly alter the incidence and frequency of mammary tumors. Combining atorvastatin (500 mg/kg diet) with either tamoxifen or bexarotene minimally altered their efficacy. Lovastatin in the doses of 100 and 400 mg/kg diet yielded similar results as atorvastatin with limited oncostatic effects administered alone, without obvious synergy with tamoxifen or bexarotene. The results of both the above-mentioned experiments with atorvastatin and lovastatin of Lubet’s group are in strong contrast to the apparent anti-neoplastic effects of atorvastatin, simvastatin, fluvastatin, and rosuvastatin observed in experiments of Kubatka’s group. The antimitotic, proapoptotic, anti-angiogenic, and antimetastatic effects of statins that have been documented

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Table 1 Different statins in the chemoprevention of rat mammary carcinogenesis.

Exp. Atorvastatin [40] Control group Atorvastatin 100 mg/kg Exp. Simvastatin [25] Control group Simvastatin 180 mg/kg Exp. Fluvastatin [38] Control group Fluvastatin 200 mg/kg Exp. Rosuvastatin [73] Control group Rosuvastatin 250 mg/kg Exp. Pravastatin [unpublished] Control group Pravastatin 100 mg/kg * **

Tumor frequency

Tumor incidence (%)

Tumor latency (days)

2.58 0.50**

79 40*

81 95

1.89 0.37*

63 26*

97 112

1.45 0.53*

70 47

105 104

1.63 1.00

74 72

96 107

4.10 3.25

80 85

74 72

Significantly different P < 0.05 vs control group. Significantly different P < 0.01 vs control group.

in vitro and in vivo, may have important clinical implications. Statins may represent a novel medical approach for cancer risk reduction or treatment. Future large clinical trials should definitively answer the question about statins’ role in carcinogenesis. Several of the ongoing studies have given initial promising results.

4. Statin use, cancer risk and cancer-related mortality in clinical studies Clinical research into the interaction between statins and cancer risk and cancer-related mortality has been ongoing for many years, but only a few strong associations were found. Epidemiologic studies of the association between statins and cancer risk and cancer prognosis have demonstrated mixed results. Some of the evidence from several clinical trials suggests that statins prevent carcinogenesis and improve the survival of cancer patients [75–77]. Recently, a prospective cohort analysis showed a reduced risk of non-Hodgkin lymphoma, melanoma and endometrial cancer [78]. On the other hand, several authors emphasized that there is evidence that a high cholesterol level can prevent cancer [79]. The safety and benefit of statins have been the subject of a controversy for several decades which was partially resolved by the positive outcome of the randomized trial of cholesterol lowering Scandinavian Simvastatin Survival Study (4S Study) [80]. The study showed that long-term treatment with simvastatin was safe and reduced mortality of patients with coronary heart disease. Moreover, the extended post-trial follow-up of participants in this trial investigating cause-specific mortality and incidence of cancer five years after closure of the trial found that the incidence of any specific type of cancer did not rise in the simvastatin group in comparison with the placebo group [81]. Causality between low-density lipoprotein cholesterol and the risk of cancer was also recently studied in a Mendelian

randomization study [82]. Genotyping was performed for PCSK9 R46L (rs11591147), ABCG8 D19H (rs11887534), and APOE R112C (rs429358) and R158C (rs7412) polymorphisms associated with reduced plasma LDL cholesterol levels. These authors found that low plasma LDL cholesterol levels were associated with an increased risk of cancer, but genetically decreased LDL cholesterol was not. Their results suggest that low LDL cholesterol levels per se do not cause cancer. Recently, meta-analyses of randomized statin trials showed that statin use and low cholesterol levels were not associated with an increased risk of several types of cancer [83]. Two meta-analyses evaluating the effect of statins on breast cancer risk showed no significant association [84,85]. In a recent prospective cohort analysis no associations between statins and colon, lung, pancreatic, breast or bladder cancer were confirmed [78]. Some clinical studies demonstrated the decreased risk of cancer mortality in various organ sites associated with the use of statins. The most consistent results are from studies regarding the patients with prostate cancer. Recently authors Yu et al. confirmed in the largest population-based study of newly diagnosed patients with non-metastatic prostate cancer that the use of statins after cancer diagnosis was associated with a 24% decrease in cancer-related mortality [77]. The use of statins after prostate cancer diagnosis was also associated with a decreased risk of all-cause mortality and distant metastasis. The mean follow-up time in this study was 4.4 years (from at least one up to 15 years). The reduced risks of cancer mortality and all-cause mortality were stronger in patients who were also treated with statins before cancer diagnosis. This study also observed dose–response relationships in terms of cumulative duration of use and cumulative dose. Not only in this study, but also in a number of patients treated with statins, there is also the uncertainty of whether patients complied with the treatment regimen.


Nielsen and colleagues published in New England Journal of Medicine (2013) results of robust Danish epidemiologic observational study that confirmed reduced cancer-related mortality in a comparison of cancer-related deaths among patients with cancer who did and did not use statins [76]. Statin use was only measured before the date of cancer diagnosis and was used to indicate statin use before and after the cancer diagnosis. Patients were diagnosed with cancer between 1995 and 2007, with follow-up until December 31, 2009. All patients were 40 years of age or older. Cancerrelated mortality was reduced by 15% among patients with cancer who were regularly taking statins. The reduced cancerrelated mortality among statin users as compared with those who had never used statins was observed for 13 from 27 cancer types. However, no dose–response relationships were observed in this study. This observational study has a number of strengths and several limitations [79,86]. There were missing data on the tumor–node–metastasis (TNM) stage in patients who did and did not receive statins. Moreover, a significantly greater percentage of the cancer patients without statin therapy had no recorded information on the TNM stage in comparison with those patients who had received statins. The TNM stage is well known to reduce the survival of cancer patients. Secondly, 70% of statin users with cancer had cardiovascular disease comorbidity, as compared with 21% of patients who had never used statins before the cancer diagnosis. Patients with cardiovascular comorbidity might die from cardiovascular cause earlier than from cancer. Despite significant associations of various cancer sites with cigarette smoking, alcohol use, other therapy and physical inactivity, these factors were not sufficiently analyzed. The data of a number of studies strongly point to hypercholesterolemia as a risk factor for some types of cancer progression. However, there is also controversial evidence that a high cholesterol level can prevent cancer and low cholesterol level is associated with cancer [79,87]. In the 1980s Williams at al. published that serum cholesterol level was inversely associated with the incidence of colon cancer and with other sites in men; these inverse associations were significant after adjustment for age, alcohol consumption, cigarette smoking, education, systolic blood pressure, and relative weight [88]. And another decade later Schuit et al. observed consistent association between serum total cholesterol and cancer in Dutch civil servants aged 40–65 during a long-term follow-up study [89]. However, there is no known absolute ‘low level’ of cholesterol associated with cancer. Sacks et al. found that women randomly assigned to receive a statin had a higher incidence of breast cancer, with one patient affected in the placebo group and 12 patients affected in the pravastatin group [90]. However, analyses of other randomized trials, including several that used pravastatin, did not confirm an increase in breast cancer risk. Worries about the associations seen in observational studies between low cholesterol levels and cancer have been overcome by findings from the latest large drug intervention trials, which do not show any increase in cancer with statin

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therapy. In 2011 Solomon and Freeman published a review of 52 population studies that reported on cholesterol and total cancer incidence and/or mortality that were published from 1972 to 2009. In total, these reports cover 79.5 million men and women aged 15–99 years from Europe, USA, Australia, New Zealand, Japan, China and Israel [91]. Thirtytwo studies report an inverse association between cancer risk and cholesterol level, no association was found in 16 studies, two provided no statistics, one was a follow-up report, and one study was largely equivocal. Studies that demonstrate excess risk usually find this association more prominently in men and, most frequently, the associated cancers are those of the liver, colon, and lungs. Many of these studies were long in duration (as long as 40 years). In 12/30 of these reports, removal of cancers that appeared early in the study either diminished or eliminated the significance of the low cholesterol-increased cancer risk association, suggesting that lower cholesterol was not the cause but the result of cancer. In the Jerusalem Longitudinal Cohort Study (1990–2010), Jacobs et al. examined whether increased total cholesterol was associated with higher mortality from age 70 to 90, and if statins had a protective effect [92]. Cox’s proportional hazards models determined mortality hazard ratios, adjusting for total cholesterol, statin treatment, gender, self-rated health, smoking, hypertension, diabetes, ischemic heart disease, neoplasm, body mass index, albumin, and triglycerides. There were no relations between cholesterol levels and mortality. The protective effect of statins observed among the very old appears to be independent of total cholesterol. The main side effects of statins after long-term administration are myopathy, rhabdomyolysis, and hepatotoxicity. The doses of statins effective in the inhibition of proliferation and inducing the apoptosis are associated with high toxicity in patients. For this reason, the use of statins as monotherapy in cancer disease appears doubtful. The combined treatment regimen of statins is supported by other findings. The molecular mechanism involved in the enhanced sensitivity of multidrug resistance cells have been explored and recently elucidated [15]. In addition to potentiating the combined administration of statins with chemotherapeutics, there are positive results from preclinical research. Lovastatin protected human endothelial cells from the geno- and cytotoxic effects of etoposide and doxorubicin [93]. Pravastatin improved cisplatin-induced nephrotoxicity in mice by the inhibition of nitrosative and oxidative stress [94]. Table 2 summarizes the effects of statins on cancer risk and/or mortality obtained from clinical studies concerning all cancer types discussed here.

5. Statins and their potential clinical implications The promising anticancer effects of statins in preclinical research have stimulated investigations into their possible clinical implications as an anticancer agent in specific cancer types. There are several clinical trials available that have

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Table 2 Statins and different cancer risk/mortality in clinical studies. Cancer

Statin

Influence on cancer risk and mortality

Reference

Breast cancer Different cancers Prostate cancer Different cancers Different cancers Different cancers Breast cancer Different cancers Different cancers Esophageal cancer Hepatocellular carcinoma Colorectal cancer Colorectal cancer Colorectal cancer Colorectal cancer

Lovastatin All statins All statins All statins Simvastatin All statins All statins All statins Pravastatin All statins All statins All statins All statins All statins Atorvastatin

No effect on cancer risk Reduce cancer mortality Reduce cancer mortality Reduce cancer mortality No effect on cancer risk and mortality No effect on cancer risk and mortality No effect on cancer risk No effect on cancer risk No effect on cancer risk Reduce cancer risk Reduce cancer risk Reduce cancer risk No effect on cancer mortality No effect on cancer risk No effect on cancer risk

[75] [76] [77] [78] [81] [83] [84] [85] [88] [95–97] [100,102,103] [113–115] [116] [117] [118]

explored the potential benefits of statins in carcinogenesis. In some cases, promising results have been reported regarding their efficacy. 5.1. Esophageal cancer, Barrett’s esophagus and statins Esophageal adenocarcinoma (EAC) is a major clinical problem, especially among patients with Barrett’s esophagus (BE). It was found that statins might prevent this cancer. A meta-analysis of several studies (13 studies in 1,132,960 patients) showed a significant (28%) reduction in the risk of esophageal cancer among patients who took statins [95]. However, there was considerable heterogeneity among studies. A subset of patients known to have BE (5 studies with 2125 patients) was associated with a significant 41% reduction of EAC risk after statins’ administration, after adjusting for potential confounders with consistent results among all studies. In another a case–control study, the examination of aspirin and statin use in patients with EAC was performed [96]. Cancer cases were compared against age-sex-matched controls. A total of 112 cases and 448 controls were enrolled. Statin use was significantly associated with the decrease of EAC incidence (also in a subset of gastroesophageal reflux disease patients). A significantly greater effect was found in the combination of statin with aspirin. Moreover, the greater cancer risk reduction was observed in patients with longer duration and higher doses of statin use. The majority of statin use overall was simvastatin (67%). The effects of simvastatin and non-simvastatin agents on EAC risk were similar. Recently, Alexandre et al. [97] investigated the association between regular use of statins and the main histologic subtypes of esophageal malignancy (EAC, esophagogastric junctional adenocarcinoma, and squamous cell cancer – ESCC). Authors identified all individuals in the UK General Practice Research Database diagnosed with esophageal

cancer from 2000 to 2009. Each patient was matched with up to 4 controls for age, sex, and practice. In total, 1126 individuals with malignancy were matched to 4192 controls. Regular statin use was inversely associated with development of EAC, esophagogastric junctional adenocarcinoma, and ESCC. The same group of authors systematically reviewed both experimental and epidemiological evidence to determine whether statins can reduce the risk of developing EAC (using the Bradford Hill criteria of causality). The cellular effects of statins on EAC cell lines have been examined in three in vitro studies and all reported anti-proliferative and pro-apoptotic effects. Two prospective cohort studies involving 1382 participants, were included in the meta-analysis of risk of EAC in cohorts with BE with statin use. The pooled effect size was 0.53 with minimal heterogeneity. Meta-analysis of three prospective studies in general population cohorts (involving 35,214 individuals), showed an effect size of 0.86 for esophageal cancer risk with prior statin use [98]. In conclusion of above-mentioned studies, statins may have clinically useful effects in preventing the development of different histologic subtypes of esophageal cancer, particularly the EAC in patients with BE. 5.2. Hepatocellular carcinoma The incidence and mortality of hepatocellular carcinoma (HCC) are increasing in most developed countries. This is a result of an aging cohort infected with chronic hepatitis B and C (HVB, HVC), and a consequence of the obesity, metabolic syndrome, and alcohol-related cirrhosis. Currently, there are no chemopreventive agents that may reduce the risk of HCC. Several commonly prescribed drugs seem promising as chemopreventive agents against HCC, including statins [99]. Singh et al. [100] conducted a systematic search in scientific databases. They included studies that evaluated the effects of statins on the risk of HCC. Totally 4298 cases of


HCC in 1,459,417 individuals were evaluated. Statin use was associated with a reduced risk of HCC, most strongly in Asian but also in Western populations. In connection with this study, chronic HBV is the dominant risk factor for HCC in most areas of Asia and sub-Saharan Africa, whereas it accounts for only 23% of HCC cases in Western countries. HVB genome integration has been associated with host DNA microdeletions that can target cancer-relevant genes; however statins can prevent potential detrimental effects of growth signaling proteins (Ras, Raf, MAPK, ERK). Likewise, HCV stimulates the nuclear factor ␬B pathway, leading to immune activation, and inflammation, which is inhibited by statins. For instance, statin use was associated with reduced risk of HCC in HVC-infected patients in the Taiwan [101]. Moreover, the protective effects of statins (particularly in Western population) may be related to modification of metabolic syndrome, insulin-mediated cell proliferation, and obesity-associated inflammation [100]. Pradelli et al. [102] reported a MEDLINE search for observational studies reporting the association between exposure to statins and risk for incident liver cancer. Five observational studies (two case-control and three cohort studies) based on 2574 cases of HCC were included. Statin treatment, compared with no treatment, was inversely related to HCC. This meta-analysis suggests a favorable effect of statins on HCC, in the absence, however, of a duration–risk relationship. Lonardo and Loria [103] discussed the methodological strengths and pitfalls of published data including three cohort studies suggesting that the use of statins may protect from the development of HCC and a single trial reporting increased survival in those with advanced HCC randomized to receive statins. They concluded that there is strong experimental evidence that statins are beneficial in chemopreventing and slowing the growth of HCC. Epidemiological and clinical data have demonstrated that non-alcoholic fatty liver disease (NAFLD) and its associated metabolic abnormalities are a risk factor for HCC. The mechanism whereby NAFLD acts as a risk for HCC are believed to include replicative senescence of steatotic hepatocytes and compensatory hyperplasia of progenitor cells as a reaction to chronic hepatic injury. Yilmaz et al. [104] reviewed that insulin resistance, inflammation as well as derangements in adipokines and angiogenic factors associated with NAFLD are closely intertwined with the risk of developing HCC. Traditional therapeutic approaches in NAFLD including metformin and statins may theoretically reduce the risk of HCC. In summary, above cited papers suggest that use of statins is associated with a reduced risk of HCC. This protective association is more pronounced in the Asian population, where the viral hepatitis is the most important risk factor for HCC. This risk reduction is also found in Western population, where HCC is predominantly associated with metabolic syndrome. Randomized clinical trials with statins in populations at high risk for HCC, especially in Asian populations with chronic HVB or HVC, are warranted [100,101].

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5.3. Colorectal cancer Colorectal cancer (CRC) is the third most common cancer in the world. Dyslipidemia is an established risk factor for many diseases, particularly cardiovascular diseases, but it is less clear whether it is associated with greater risk of cancer. There is clear evidence that individuals with metabolic syndrome (MetS) with its systemic and hormonal effects or patients with type 2 diabetes mellitus are at increased risk of CRC [105–107]. MetS is characterized by several components (abdominal obesity, high blood pressure, dyslipidemia, impaired glucose tolerance, and other). In particular, the dyslipidemia component is linked to chronic low-grade inflammation [108], oxidative stress [109], and insulin resistance [110], all of which may enhance the carcinogenesis. Recently, Agnoli et al. [111] concluded from a case–cohort study in 34,148 participants that elevated plasma total- and LDL-cholesterol may be the risk factor for colorectal cancer, especially all colon and distal colon cancer. Yang et al. [112] conducted a retrospective cohort study of 36,079 patients with colon cancer to determine the effect of MetS and its components on overall survival and recurrence-free rates. MetS had no apparent effect on colon cancer outcomes, probably because of the combined adverse effects of elevated glucose/DM and hypertension and the protective effect of dyslipidemia in patients with non-metastatic disease. The authors concluded that patients may benefit from more intensive surveillance and/or broader use of adjuvant therapy (e.g. insulin-lowering agents and statins). There is a long-time discussion about whether statins have preventive effects against CRC. Forty-two studies were included in the evaluation of Liu et al. [113]. Overall, statin use was associated with a modest reduction in the risk of CRC. When the results were stratified into subgroups, significant decrease in CRC risk was found in observational studies, rectal cancer, and lipophilic statins. Long-term statin use did not appear to significantly affect the risk of CRC. In another study ninety-nine patients with primary rectal adenocarcinoma underwent neoadjuvant therapy then protectomy. Statin therapy was associated with an improved response of rectal cancer (overall survival, disease-free survival, mortality, and local recurrence) [114]. A total of 40 studies, involving more than eight million subjects, contributed to the analysis of Lytras et al. [115]. Three separate meta-analyses were conducted. A modest reduction in the risk of colorectal cancer with statin use was observed, which was not statistically significant among randomized controlled trials, but reached statistical significance among cohort studies and case–control studies. On the other hand, there are also clinical studies with nonconvincing results about antitumor effects of statins in CRC. Statin use during and after adjuvant chemotherapy was not associated with improved disease-free survival, recurrencefree survival, or overall survival in patients with stage III colon cancer (842 patients), regardless of KRAS mutation status [116]. In another study (evaluated two large prospective

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cohort studies), the investigators found no association with the risk of overall and KRAS wild-type CRC and statin users [117]. Data from multicenter, phase II trial involving subjects 40 years or older, with previously resected colon cancer or multiple/advanced colorectal adenomas, do not provide convincing evidence of CRC risk reduction from 6-month interventions with atorvastatin, sulindac, or prebiotic dietary fiber. However, statistical power in this study was limited by the relatively small sample size [118]. Regarding to colon carcinogenesis, there are several promising results with statin use in preclinical research. Simvastatin and pravastatin were effective against malignant colon cancer cell lines [119]. Atorvastatin alone and in combination with suberoylanilide hydroxamic acid demonstrated chemopreventive activity in 1,2-dimethylhydrazine-induced colon carcinogenesis in Swiss-Webster mice [120]. Lovastatin administration reduced primary tumor and metastasis in the NOG mouse model of human malignant mesothelioma in vivo [121]. In vitro studies showed that lovastatin administration induced cytostatic effects as per reduced cell viability and cell migration in ACC-MESO-1 cells. In vivo study with F344 rats found that low-dose atorvastatin with sulindac or naproxen were useful combinations in the prevention of colon carcinogenesis [122]. And finally using colon cancer models, different statins were confirmed as agents – with differentiating effects in xenograft mouse model [123], which may overcome drug resistance [63], and which suppress intestinal polyps in Min mice [72]. In conclusion, the understanding of the underlying pathophysiology that links the MetS and colorectal cancer may play an important role in developing new strategies in the cancer risk reduction and/or treatment. Several meta-analyses suggest a modest decrease in relative risk of CRC in statin users. These preventive effects were more pronounced in rectal cancer and lipophilic statins. Further targeted research is warranted.

It was found that primary care physicians harbor significant hepatotoxicity concerns, and these concerns act as a barrier to statin utilization [128]. The evaluation of seven trials with 42,848 patients included in meta-analysis demonstrated increase in the levels of liver enzymes [129]. Four trials were included in another analysis. Intensive-dose therapy with atorvastatin or simvastatin (80 mg/day) was associated with an increased risk for abnormalities on liver function testing [130]. On the other hand, a meta-analysis of de Denus et al. [131] found that pravastatin, lovastatin, and simvastatin at low-to-moderate doses are not associated with a significant risk of liver function test abnormalities. Smeeth et al. [132] found an increased risk of incident liver disease in the first year after the index date, but little or no increased risk after this time. HippisleyCox et al. [133] found an increased risk of liver enzyme changes in a population based cohort study (more than 2 million patients). Incidence of liver disorders in these two large prospective studies ranged from 44 to 120 per 10,000 individuals. On the other hand, there are studies which found that statins can improve the adverse outcomes of other conditions commonly associated with non-alcoholic steatohepatitis (for example hyperlipidemia, diabetes mellitus, and metabolic syndrome). The statin use in patients with non-alcoholic steatohepatitis may be justified [134,135]. However future targeted treatment strategies may be needed. In summary, the absolute excess risk of the observed harmful unintended effects of statins on liver is relatively small compared to the beneficial effects of statins on major cardiovascular events. Moderate-dose statin therapy may be the most appropriate choice for achieving CVD (or cancer) risk reduction in the majority of individuals, whereas intensivedose statin therapy may be reserved for those at highest risk. Further studies are needed to develop utilities to individualize the risks so that patients at highest risk of adverse events can be monitored closely.

5.4. Statins’ unintended effects and hepatotoxicity Since the start of widespread use of statins in clinical practice, numerous observational studies in North America and Europe have provided contradictory results on the effect of statins on a wide range of unintended effects [124–126]. In systematic review and meta-analyses of Macedo et al. [127] a ninety studies were included. Statins were associated with lower risks of dementia and cognitive impairment, venous thrombo-embolism, fractures and pneumonia (marked heterogeneity of effects across studies remained). Statin use was not related to any increased risk of depression, common eye diseases, renal disorders or arthritis. There was evidence of an increased risk of myopathy, diabetes mellitus, and raised liver enzymes. It is well documented that statin use is associated with adverse effects that include elevations in liver function tests and liver toxicity. In many cases, statins are not prescribed or they are underprescribed because of fears of injury to the liver.

6. Conclusions and future perspectives Strong evidence about the anti-cancer effects of statins in preclinical research has stimulated the investigation of their potential as drugs for cancer therapy. However, there are several clinical questions about the role of statins in carcinogenesis, e.g. the tumor type most sensitive to statins or the type of statin most effective in specific cancer disease, also the optimal statin regimen (continuous, low-dose, or highdose). Comprehensive in vitro studies have been performed to explore the benefits of statin use as part of a combined treatment regimen. In the future, it appears doubtful that statins will be administered as monotherapy in cancer prevention and treatment. Interplays between statins and cancer in a clinical setting are complicated and require more prospective longterm follow-up studies. Although the increasing number of


ongoing clinical trials is encouraging, relevant data for the effects of statins on the prognosis of cancer patients and secondary chemoprevention are still lacking. There is consistent evidence about the association of statins and reduced risk and cancer mortality of prostate cancer in clinical practice. Recently, promising results have been reported regarding the reduction of risk in esophageal and colorectal cancer, and hepatocellular carcinoma. Until now, most of the published clinical studies had a short follow-up period or their results were not sufficiently adjusted to cancer risk factors and comorbidities. Observational studies demonstrated beneficial effects of statins on various health outcomes surprisingly often, whereas randomized, controlled trials do not. Such discrepancies between observational studies and randomized, controlled trials have also been noted in several clinical situations. Before launching randomized, controlled long-term trials assessing the effects of statins, existing observational studies must be seriously discussed. Moreover, better subgroup analyses of people with strong risk factors for cancer must be explored in additional observational studies. Despite significant associations of various cancer sites with cigarette smoking, alcohol use, other therapy with cancer-protective effects and physical inactivity, these factors were not analyzed in many trials. Some investigators suggest that long-term studies comparing patients receiving statins and individuals with similar cholesterol levels not receiving such therapy may be useful. Until now, there is no consensus regarding the clinical effects of statins for carcinogenesis and cancer mortality.

Conﬂict of interest The authors declare no conflict of interest.

Reviewers Dr. Chih-Sheng Chu, Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. Dr. Amedeo Lonardo, Dipartimento Integrato di Medicina, Endocrinologia, Metabolismo e Geriatria, UOC di Medicina Interna, I-41126, Modena, Italy.

Acknowledgements This study was supported by the Scientific Grant Agency of the Ministry of Education of the Slovak Republic under the contract no. VEGA 1/0043/12, VEGA 1/0906/14, and by a grant from the European Regional Development Fund – Project FNUSA-ICRC (No.CZ.1.05/1.1.00/02.0123), Grant Agency of the Czech Republic (Nos. GA13-19910S and

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GBP302/12/G157) and Ministry of Education, Youth and Sports of the Czech Republic (No. 7AMB13FR011).

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Biographies Peter Kubatka, Sc.D., Ph.D. is an experimental oncologist at Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Slovak Republic. He graduated in Biology in 1997 from the University of P.J. Safarik in Kosice, Slovakia. He has a particular interest in the experimental breast cancer. He evaluated the chemopreventive effectiveness of retinoids, non-steroidal anti-inflammatory drugs, selective estrogen receptor modulators, aromatase inhibitors, antidiabetics, statins, different phyto-substances, and melatonin in mammary carcinoma model. Dr. Kubatka has authored or co-authored over 50 original manuscripts. Peter Kruzliak studied at Medical Faculty of Comenius University in Martin, Slovak republic where he obtained his MD in 2008. Since that time he started his carrier as a researcher in Slovak Academy of Sciences in Bratislava at the Department of Normal and Pathological Physiology. He obtained his “Master of Science” in 2012. His research activities comprises of molecular cardiology and genetics, molecular biology of atherosclerosis, molecular and translational oncology, stem cells biology and therapy, arterial hypertension, myocardial ischemia–reperfusion injury and heart failure. He was awarded “Slovak Society of Internal Medicine” for best publication in 2010 and “Slovak Society of Cardiology Young Investigator Award” in 2011. Currently, he is a Senior Researcher at the International Clinical Research Center (ICRC) in Brno. He had published many articles. Vladimir Rotrekl received his PhD in Biochemistry at the Masaryk University in Czech Republic in 2000. Major part


of his PhD program he spent at the Max Planck institute in Cologne, Germany, where he was studying plant hormone specific glycosylases. Later he got interested in mammalian genome integrity maintenance and repair mechanisms related to cancer, aging and human mutagenesis at the Health Science Center in San Antonio, Texas, USA, where he later received a faculty position. He was involved in the identification of the failing DNA repair mechanisms contributing to the elevated mutagenesis in germ cells connected with parental age effect. Later he moved back to his homeland where he works as assistant professor of Biology at the Faculty of Medicine, Masaryk University. His research group is focused on the genome integrity maintenance in human embryonic stem cells and induced pluripotent stem cells and mainly heart disease modeling using patient specific induced pluripotent stem cells and human embryonic stem cells. So far during his career he published scientific reports in the peer reviewed international journals with cumulative IF over 30.

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Sarka Jelinkova graduated at the Masaryk University, Faculty of Science. Her diploma project involved analysis of the molecular mechanisms underlying the effect of statins on human embryonic stem cells and induced pluripotent stem cells. She recently joined PhD program studying the molecular aspects of statin effect on cardiac disease models derived human embryonic stem cells and patient specific induced pluripotent stem cells in the research group of Vladimir Rotrekl. Beata Mladosievicova, M.D., Ph.D. serves as head of department of Clinical Pathophysiology, Comenius University in Bratislava, Slovak Republic. Her research is focused on pathophysiology of tumorigenesis and cardiooncology. She published a numerous original papers in the peer-reviewed international journals. She is a member of International CardioOncology Society (ICOS), International Society of Pediatric Oncology (SIOP), and American Society of Clinical Oncology (ASCO).

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