Statins are one of the world’s most commonly prescribed drugs (1). They are used to lower cholesterol level by inhibiting hydroxy-methylglutaryl-coenzyme A reductase (HMG-CoAR), which is an essential enzyme for synthesis of endogenous cholesterol. Clinical benefits of statins therapy may be greater than changes in lipid profile.
The non-lipid-lowering or pleiotropic effects of statins involve improving endothelial function, stabilization of atherosclerotic plaques, modulation of inflammatory response and regulation of coagulation and fibrinolysis process. Statins are beneficial in the primary and secondary prevention of coronary heart disease, prevention of ischemic stroke and diabetic vascular complications. It is probable that in the nearest future this group of drugs will find therapeutic application not only in cardiovascular disorders, but also in many other diseases (2,3).
Interesting are the facts about their beneficial impact on inhibiting some of the tumors, including breast cancer. The studies are only preclinical. Hitherto gathered information are promising. In the future the statins may be an important alternative for cancer therapy.
Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis. There are several potential mechanisms connecting cholesterol metabolism pathways with a process of carcinogenesis. HMG-CoA reductase is the major rate-limiting enzyme in cholesterol synthesis. Statins as inhibitors of HMG-CoAR prevents the conversion of HMG-CoA to mevalonate (MVA). Dysregulation of the MVA pathway reveal oncogenic potential by promoting the transformation of normal or precancerous cells. Interestingly statins are able to cooperate with Ras protein – common oncogene in human cancer (4).
In vitro and in vivo experiments showed cytostatic effect of statins in numerous cancer cell lines (5). Recently, it has been suggested that statins induce apoptosis and necrosis in several experimental settings including that of breast cancer (6). Induction and enhancement of reactive oxygen species (ROS) formation has been explored as a possible cause of statins cytotoxicity (7).
It may also play a role in the pro-apoptotic and anti-proliferative effects on breast cancer cells by stimulation of nitric oxide synthesis (8). Additionally, statins are known to influence cell cycle regulatory proteins by activation caspase-3, modulation of expression of transcriptional factor NF-kB (9) and several cyclin-dependent kinases (CDK1, CDK2) by the increased expression of p21 and p27 cyclin kinase inhibitors (10).
Recently, scientists from the Columbia University discovered that p53 mutation correlates with highly expressed sterol biosynthesis genes in human breast tumors what implicates the mevalonate pathway as a therapeutic target for tumors bearing this mutation (11). Another study suggested statin treatment following breast cancer diagnosis decreases the risk of recurrence (12,13).
Skeletal system is a common localization of primary breast cancer metastases. Studies show that simvastatin acts as an inhibitor of osteolytic lesions formation. Expression of the cancer stem cell marker, CD44 in a mouse model of breast cancer leads to invasive potential of the tumor cells. Statins significantly decrease the expression of this protein (14).
Substantial data from the last few years studies reveal tumor-suppressive effects of statins in several human cancers. The molecular mechanisms by which statins block cancer cell growth remain unclear (15). There is strong laboratory evidence on statins anticancer effects in various cell lines. Most of these studies are in stage of preclinical trials however present outcomes are promising. It is a chance that statins become a new alternative treatment in breast cancer therapy.
Written by: Justyna Markowicz, Ewelina Grywalska
1. Most Commonly Prescribed Drugs, Blue Cross and Blue Shield of Texas , Effective January 1, 2011. Available at: www.bcbstx.com.
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