*Agata Tomaszewska1, Monika Ostrowska1, Jadwiga Snarska2, 3, Radosław Grabysa1
The role of statins in chemoprevention of colorectal carcinoma
Rola statyn w chemoprewencji raka jelita grubego
1Department of Internal Diseases and Gastroenterology, Independent Public Health Care Facility of the Ministry of the Interior, Warmian-Mazurian Oncology Centre, Olsztyn
2Department of General Surgery, Faculty of Medical Sciences of the University of Warmia and Mazury, Olsztyn
3Independent Public Health Care Facility of the Ministry of the Interior, Warmian-Mazurian Oncology Centre, Olsztyn
Rak jelita grubego jest jednym z najczęstszych nowotworów na świecie zarówno pod względem zachorowalności, jak i śmiertelności. W prospektywnych badaniach epidemiologicznych jednoznacznie udowodniono, że dieta bogata w tłuszcze nasycone i wynikające z tego zaburzenia gospodarki lipidowej powodują zwiększone ryzyko wystąpienia tego nowotworu. Chemoprewencja to zastosowanie leków i naturalnych zwia?zków w celu zapobiegania rozwojowi nowotworów łagodnych i złos?liwych. Działanie chemoprewencyjne w zakresie kancerogenezy opierać się może na hamowaniu procesów zapalnych, obniżaniu stężenia wolnych rodników w surowicy krwi, wstrzymywaniu podziałów komórkowych oraz promowaniu różnicowania komórek. Ze względu na wzrastającą częstość występowania nowotworów jelita grubego szansa chemoprewencji tego nowotworu wzbudza duże zainteresowanie onkologów i jest przedmiotem licznych badań epidemiologicznych i klinicznych. W pracy przedstawiono aktualny stan wiedzy dotyczący możliwości chemoprewencji tego nowotworu z wykorzystaniem powszechnie stosowanej we współczesnej farmakoterapii chorób układu sercowo-naczyniowego terapii z wykorzystaniem statyn, których liczne plejotropowe właściwości mogą w konsekwencji wpłynąć pozytywnie na obserwowane niekorzystne wskaźniki epidemiologiczne dotyczące raka jelita grubego.
Colorectal carcinoma is one of the most common cancers in the world both in terms of prevalence and mortality. Prospective epidemiological studies have clearly demonstrated that a diet rich in saturated fats and its related lipid metabolism disorders increase the risk of this disease. Chemoprevention is the use of drugs and natural compounds to prevent benign and malignant cancers. Chemopreventive effects with respect to carcinogenesis may be based on: inhibiting inflammatory processes, lowering serum levels of free radicals, suppressing cell divisions, and promoting cell differentiation. Because the prevalence of colorectal carcinoma is growing, a chance for potential chemoprevention raises oncologists’ interest and is a subject of various epidemiological and clinical studies. This paper presents the current state of knowledge regarding potential chemoprevention of this cancer using statin therapy, which is broadly implemented in the present-day pharmacotherapy for cardiovascular diseases. Various pleiotropic effects of statins may in consequence have a positive influence on currently observed negative epidemiological indices of colorectal carcinoma.
Epidemiology and aetiology of colorectal carcinoma
Growing prevalence of cancer in general remains one of the principal health-related problems of the contemporary world. The analysis of statistical indices regarding this issue supports the fact that, of all neoplastic diseases, colorectal carcinoma (CRC) is currently the third cancer in terms of prevalence and the second cancer in terms of mortality. It is estimated that in 2018 there were 1.8 million new CRC cases and 881,000 deaths from this disease (1).
The aetiology of CRC currently involves cellular mechanisms, such as microsatellite instability (MSI) with island methylator phenotype (CIMP) and chromosomal instability (CIN). These mechanisms are linked with cellular changes on the epigenetic and genetic level. They lead to the impairment of cellular pathways, such as cellular repair and transformation, which in consequence may result in the development of colorectal carcinoma (2). The above-mentioned mechanisms will not be discussed in detail as they are not the main subject of this article. It must be noted that irrespective of these cell mechanisms, the development of CRC is associated with lifestyle, mainly eating habits. Prospective epidemiological studies have clearly demonstrated that a diet rich in saturated fats and its related lipid metabolism disorders increase the risk of this disease (3). These studies have also revealed that elevated levels of total cholesterol and other lipoproteins are associated with an increased risk of CRC (4).
In this paper, we briefly discuss the results of the latest studies, which indicate that the risk of CRC may be reduced by common use of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (further referred to as statins) in hypolipidemic therapy.
Chemoprevention of colorectal carcinoma
Chemoprevention is the use of drugs and natural compounds in order to prevent benign and malignant cancers. Chemopreventive effects with respect to carcinogenesis may be based on: inhibiting inflammatory processes, lowering serum levels of free radicals, suppressing cell divisions, and promoting cell differentiation. Chemoprevention may slow carcinogenesis by altering gene expression and modifying intracellular signal transduction pathways (5).
Because the prevalence of colorectal carcinoma in modern-day societies is growing, potential chemoprevention raises oncologists’ interest and is a subject of various clinical trials. These trials have brought a lot of information that is interesting from the practical point of view, but it is still insufficient to formulate specific guidelines regarding statins that could be used for this purpose.
One of the first observations to have confirmed potential CRC prevention using broadly available drugs concerned positive effects of acetylsalicylic acid (ASA), which is commonly used in medicine. This has been shown in the UK-TIA Aspirin Trial which confirmed that 5-year use of ASA significantly lowers the risk of CRC in the studied population (6). Nevertheless, because of the adverse safety profile, this drug has not been included in the current guidelines of academic societies (7).
In the past years, more and more attention has been drawn to the role of the metabolism of calcium and vitamin D3 in cell division and thus in the mechanisms leading to carcinogenesis. Peters et al. (8) observed an inverse correlation between the serum level of vitamin D3 25-OH and the risk of colorectal adenoma in the population of patients with this disease. The authors conclude that the increase in vitamin D3 25-OH concentration by every 10 ng/mL entails a 26% reduction in the risk of colorectal adenoma. They also underline that numerous additional studies are required to formulate more precise conclusions regarding dosage and indications for use.
Selenium, with its antioxidant effects, is the element that may bring some benefits in CRC chemoprevention. Clark et al. (9) examined 1,312 patients with basal cell carcinoma of the skin and observed that CRC was much rarer in patients who used dietary supplements with this microelement at a dose of 200 μg daily. Drugs of the 5-ASA group, i.e. amine salicylic acid derivatives, which inhibit inflammation via a non-selective cyclooxygenase blockage, are well-explored substances currently used for the treatment of inflammatory processes within the gastrointestinal tract. Moreover, these compounds promote cell apoptosis and inhibit free radical production via TNF-α (tumour necrosis factor α) and NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), thereby modifying inflammatory and proliferative processes (10). In a meta-analysis of studies on therapy involving the use of these substances, which was conducted in 2005, a conclusion was drawn that the risk of cancer and dysplasia is lower in patients using 5-ASA (11). Munkholm et al. (12) believe that a daily dose of mesalazine, which has chemopreventive effects in CRC prevention, should range from 1.2 to 2.4 g.
The mechanisms of oncoprotective action of statins
Statins are substances that lower serum concentrations of LDL cholesterol, total cholesterol and triglycerides by inhibiting β-hydroxy β-methylglutaryl-coenzyme A (HMG-CoA) reductase, thereby leading to increased expression of low-density lipoprotein receptors on hepatocytes (13). These compounds exert a number of additional extra-lipid properties, described as pleiotropic, including: antiproliferative, antithrombotic, anti-inflammatory, antioxidant and stabilizing effects on the atherosclerotic plaque and vascular endothelium (14).These drugs are currently one of the pillars of the modern-day pharmacotherapy in cardiovascular diseases and are among the most frequently prescribed products worldwide. The study whose results started the triumphant career of statins in the contemporary medicine was published in 1994 and is commonly known under the acronym “4S” (Scandinavian Simvastatin Survival Study). It revealed a decrease in overall mortality after simvastatin treatment in patients with hypercholesterolemia and coronary artery disease (15). In the further 8-year follow-up of the population included in this clinical trial, it was observed that the patients who used simvastatin for the whole study period were characterized by a tendency to a lower incidence of cancer (16).
The mechanism underlying the “ocoprotective” effects of statins is not entirely clear. Apart from the extra-lipid, mainly proliferative properties listed above, statins that contain carboxylic acid chains also exert an inhibiting effect towards histone deacetylases (HDAC), thereby affecting cell signalling pathways, inhibiting the cell cycle and angiogenesis, and inducing apoptosis of neoplastic cells (17).
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