How do statins fight cancer?

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Abstract​

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

 

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INTRODUCTION​

Statistics published in September 2018 by the World Health Organization revealed that cancer is responsible for one in six deaths worldwide. The most diagnosed and deadly types of cancer are lung cancer (LC), breast cancer (BC), colorectal cancer (CRC) and prostate cancer (PC). The most common risk factors responsible for cancer occurrence include smoking, obesity, unhealthy diet, alcohol consumption and viral infections[1]. Cancer, which is represented by a large number of conditions, is defined as an uncontrolled proliferation of cells that possess metastatic properties. These cells are characterized by changes in their activity, such as the suppression of apoptotic mechanisms, the disruption of cell adhesion and signaling, and changes that occur as a result of genetic mutations[2].

Lately, high cholesterol levels have been associated with the development of some types of cancer, i.e., CRC, PC and BC[3]. The literature describes two main paths through which cholesterol contributes to cancer onset. The first one involves the fundamental role of cholesterol in processes such as cell adhesion and signaling, necessary for normal cell functioning, while the second one refers to its function as a precursor in the synthesis of sex hormones and other isoprenoid intermediates, responsible for the development of particular types of cancer[4,5]. The latest treatment directions suggest that this field should be further explored due to the benefits that cholesterol-lowering drugs can bring in cancer treatment[4].

 

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Statins are the first cholesterol-lowering agents discovered. Due to their significant ability to reduce cholesterol blood levels, international guidelines acknowledge statins as a first-line treatment for hypercholesterolemia[6]. By inhibiting the synthesis of cholesterol and its metabolites[7,8], statins have shown antiproliferative effects in various types of cancer[3]. A number of observational studies reported a risk reduction in the onset of cancer, or improvements in the outcomes of cancer, in statin users. The variable efficacy of different statins is related to their distinct physiochemical properties and the length of treatment[9]. Many in vitro and in vivo studies performed on different types of cancers underlined the molecular mechanisms through which statins inhibit cancer cell proliferation and metastasis[10]. These mechanisms were considered the basis for introducing statins in cancer treatment and prevention[8,11]. The antiproliferative effects of statins are a result of both inhibition of the mevalonate pathway and their pleiotropic effects, i.e., antioxidant, anti-inflammatory and immune modulatory properties, with a major impact on patient survival and cancer recurrence[10,12].

The purpose of this review was to present the latest studies regarding the antiproliferative effects of statins. The paper is divided into two parts. The first section is dedicated to reviewing the latest published preclinical studies, highlighting the main mechanisms through which statins exert their anticancer properties. In the second part, several observational studies and clinical trials on statins, as single therapy or in combination with anticancer therapies, are summarized as future lines of research in cancer prevention/treatment.

 

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MECHANISM OF ACTION OF STATINS​

Cholesterol along with isoprenoid intermediates are synthesized through the mevalonate pathway. In this process, 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) is converted into mevalonate viaHMG-CoA reductase. Statins, due to their structural similarity to HMG-CoA, are competitive inhibitors of HMG-CoA reductase, and thereby have the ability to suppress cholesterol synthesis[13-15]. The affinity of statins for HMG-CoA reductase is in the nanomolar range, compared to the natural substrate whose concentration needs to be in the micromolar range[15]. Statins mainly act in the liver, where they induce an overexpression of low density lipoprotein (LDL) receptors at the surface of hepatocytes, thereby increasing the uptake of circulating LDL[15,16]. Through this mechanism, statins reduce lipoprotein blood levels, and consequently decrease the risk of developing cardiovascular diseases and their related complications[14].

The potency of these drugs is highly influenced by their physicochemical properties. Lipophilic statins, i.e., simvastatin, mevastatin, lovastatin, and pitavastatin, can easily cross cell membranes by diffusion, while hydrophilic statins, i.e., pravastatin, need special membrane transporters[12,15,17,18]. Another difference arises due to their molecular structure. Synthetic statins, i.e., rosuvastatin, pitavastatin, atorvastatin and lovastatin, possess a fluorophenyl group which confers them the ability to form an additional linkage to HMG-CoA reductase; therefore, exhibiting a more potent inhibition. On the other hand, simvastatin, pravastatin, mevastatin and lovastatin are obtained through fungal fermentation, and contain a decalin ring[13,15,18]. In addition, simvastatin and lovastatin are used as inactive prodrugs which makes them 100-fold more lipophilic than pravastatin. After oral administration, these prodrugs are metabolized by CYP enzymes to a hydroxy-acid active form[19]

 

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PRECLINICAL STUDIES EVALUATING THE ANTICANCER EFFECTS OF STATINS​

Since the first reports in the late 1990s on the ability of statins to influence cancer progression, their anticancer properties have been extensively documented in a wide range of cancer cell lines and tumor-bearing animal models. Several preclinical studies support the anticancer effects of statins against various types of tumors, including liquid tumors such as myeloma and leukemia, and solid tumors[20]. The possible underlying mechanisms that account for the anticancer effects have been reported in numerous in vitro studies. It has been shown that their anticancer properties result from the suppression of tumor growth, induction of apoptosis and autophagy, inhibition of cell migration and invasion, and inhibition of angiogenesis[21-23].

This chapter outlines the current state of knowledge concerning the anticancer effects of statins from in vitro and in vivo preclinical studies. However, due to the vast data available in the literature regarding this subject, we will focus on presenting the most recent reports.

 

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In vitro studies​

Some of the most recent results from in vitro studies on statin anticancer activity are presented in Table Table1.1. By examining the results reported in the literature, several conclusions can be drawn, which are in agreement with findings previously reported by Osmak et al[11], Ahmadi et al[24], and others.

Table 1​

In vitro studies on the anticancer potential of statins

[TR]
[TD]​

Cancer type

[/TD]
[TD]Cancer cell line[/TD]
[TD]Statin[/TD]
[TD]Observations[/TD]
[TD]Changes in intracellular signaling pathways[/TD]
[TD]Ref.[/TD]
[/TR]
[TR]
[TD]​

Hepatoma

[/TD]
[TD]HepG2, Hep3B[/TD]
[TD]Simvastatin[/TD]
[TD]Inhibition of cell growth in a dose- and time-dependent manner; G0/G1 cell cycle arrest; Apoptosis[/TD]
[TD]AMPK activation and STAT3/Skp2 axis suppression, inducing p21 and p27 accumulation[/TD]
[TD][21][/TD]
[/TR]
[TR]
[TD]​

Ovarian cancer

[/TD]
[TD]Hey, SKOV3[/TD]
[TD]Atorvastatin[/TD]
[TD]Dose-dependent antiproliferative effect (1-250 µmol/L); Decrease in size and density of the cancer cells, and colony forming ability (at 150 µmol/L); G1-phase cell cycle arrest and S-phase decrease (at 150 µmol/L); Induction of apoptosis; Increased ROS levels in a dose-dependent manner; Induction of autophagy; Inhibition of cell adhesion and invasion[/TD]
[TD]Inhibition of Akt/mTOR and activation of MAPK pathway; Decreased Mcl-1 expression, variable effect on Bcl-2 expression, increased cleaved PARP protein expression; Increased expression of cellular stress protein (PERK and Bip) (at 150 µmol/L); Reduced expression of VEGF protein and MMP-9[/TD]
[TD][22][/TD]
[/TR]
[TR]
[TD]​

Breast cancer

[/TD]
[TD]SUM149, SUM159, MDA-MB-231[/TD]
[TD]Simvastatin[/TD]
[TD]Inhibition of proliferation, decrease in S-phase and increase in G1/S-phase arrest; Suppression of cell migration; Decrease in tumor sphere formation[/TD]
[TD]Down-regulation of phosphorylated FOXO3a in SUM149 and SUM159 cells; Variable effect on total FOXO3a expression[/TD]
[TD][43][/TD]
[/TR]
[TR]
[TD]​

Endometrial cancer

[/TD]
[TD]ECC-1, Ishikawa, primary cultures of endometrial cancer cells[/TD]
[TD]Simvastatin[/TD]
[TD]Dose-dependent antiproliferative effect in both cancer cell lines (0.01-50 µmol/L), and in 5/8 primary cultures; G0/G1-phase cell cycle arrest, decreased S-phase in ECC-1 cells; Decreased HMG-CoA reductase activity; Induction of apoptosis; Increased DNA damage, cellular oxidative stress; Reduced cell adhesion and invasion[/TD]
[TD]Inhibition of MAPK pathway, differential effects on the Akt/mTOR pathway; Increased cleaved caspase-3, decreased Bcl-2 expression, unmodified Mcl-1[/TD]
[TD][20][/TD]
[/TR]
[TR]
[TD]​

Osteosarcoma

[/TD]
[TD]MNNG/HOS[/TD]
[TD]Simvastatin[/TD]
[TD]Dose- and time-dependent antiproliferative effect (0.5-64 µmol/L); Dose-dependent morphological changes in treated cells: Cell shrinkage, loss of intercellular contact, reduced cell adherence, floating shapes; Dose-dependent suppression of cell migration, G0/G1-phase cell cycle arrest (16 µmol/L), and apoptosis[/TD]
[TD]Dose-dependent down-regulation of MMP-2 and MMP-9; Down-regulation of cyclin D1, CDK2 and CDK4, up-regulation of CDKIs, p21 Cip1 and p27 Kip1; Decrease in PI3K and phospho-Akt expression, while total AKt remained unmodified, up-regulation of Bax and cleaved PARP expression, decreased Bcl-2 expression[/TD]
[TD][44][/TD]
[/TR]
[TR]
[TD]​

Lung adenocarcinoma

[/TD]
[TD]A549, H1299, PC9, HCC827, H1975, H1435, PE8sc, CL1-0, Bm7, and immortalized normal lung epithelial cells (HBEC3KT)[/TD]
[TD]Simvastatin[/TD]
[TD]Higher cytotoxicity against LC cells with p53 mutation; Dose-dependent apoptosis; Reduced lipid rafts in mutant p53-bearing LC cells; Reduction in the migration distance; Promotes the nuclear transport of mutant p53 in Bm7 and H1435 cells[/TD]
[TD]Increased levels of cleaved PARP and cleaved caspase-3; No difference in the level of LC3-II; Decreased level of p53, and increased level of high molecular weight HSP-40[/TD]
[TD][45][/TD]
[/TR]​

Open in a separate window
MAPK: Mitogen-activated protein kinase; ROS: Reactive oxygen species; HMG-CoA reductase: 3-hydroxy-3-methylglutaryl-coenzyme A reductase; AMPK: AMP-activated protein kinase; STAT3: Signal transducer and activator of transcription 3; skp2: S-phase kinase associated protein 2; Akt: Protein kinase B; mTOR: Mammalian target of rapamycin; PARP: Poly (ADP-ribose) polymerase; VEGF: Vascular endothelial growth factor; MMP: Matrix metalloproteinase; CDK: Cyclin-dependent kinase; CDKI: Cyclin-dependent kinase inhibitor; PI3K: Phosphoinositide 3-kinase; LC3: Microtubule-associated protein 1A/1B-light chain 3.

 

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Firstly, it appears that the antitumor potential depends on the physicochemical properties of the statins, more precisely their lipophilicity. The chemical structure of the molecule dictates the solubility of the statin, which in turn will affect the pharmacokinetic profile[19,23,25]. The lipophilicity promotes access to different tissues, including cancer cells. Statins are taken up into cells by the organic anion-transporting polypeptide OATP1B1 mainly expressed by hepatocytes and for lipophilic statins also by passive diffusion through the membrane. As a result, hydrophilic statins show an increased affinity for hepatic tissue, but not for other tissues. However, lipophilic statins achieve higher levels in extrahepatic tissues where they interfere with the synthesis of cholesterol[19,24,26]. Several in vitro studies on various cancer cell lines have reported lower anticancer efficacy for hydrophilic statins as opposed to lipophilic statins. Beckwitt et al[27] assessed the anticancer activity of four statins, namely atorvastatin, simvastatin, rosuvastatin, and pravastatin, on four types of cancer cell lines derived from primary tumors: Breast (MCF-7 and MDA-MB-231), prostate (DU-145), brain (SF-295), and melanoma. Atorvastatin displayed the highest antitumor effect, while pravastatin had the lowest efficacy at suppressing tumor growth in all the above-mentioned cell lines. Furthermore, rosuvastatin was less potent than atorvastatin, even though the former shows similar affinity for the enzyme HMG-CoA reductase. Simvastatin, on the other hand showed similar efficacy to atorvastatin[27]. Consistent with these findings, another study demonstrated that lipophilic simvastatin significantly inhibited the proliferation of esophageal adenocarcinoma OE-19 cells and esophageal squamous cell carcinoma Eca-109 cells, at concentrations of 30 µmol/L, accompanied by the down-regulation of COX-2 and PGE2 in both cancer cell lines, in a dose-dependent manner. However, hydrophilic pravastatin had no obvious suppressive effect on tumor growth in the two investigated esophageal cancer cell lines[28]. In pancreatic cancer cell lines (PA-TU-8902, MiaPaCa-2, BxPC-3), except for pravastatin, all investigated lipophilic statins, at a concentration of 12 µmol/L, displayed significant antiproliferative activity. Cerivastatin and simvastatin proved to be the most effective in suppressing tumor growth, followed by fluvastatin and lovastatin[29]. Jiang et al[25] also proved the superior anticancer effect of lipophilic statins on BC (MDA-MB-231, MDA-MB-432, MDA-MB-435) and brain cancer (A172, LN443, U87, U118, U251), compared to hydrophilic rosuvastatin and pravastatin. Furthermore, the research group proved that the in vitro IC50 of cerivastatin and pitavastatin can be achieved at therapeutic doses of 0.2-0.4 mg/d for cerivastatin, and 1-4 mg/d for pitavastatin, respectively. The clinical relevance of these observations is that for these two statins, the doses needed to inhibit tumor growth are in the same range as those used to control cholesterol levels[25].

 

[UltimaOnline]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443827/

 

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