**2. Statins pleiotropic effects**

Statins are among the most commonly prescribed medicines worldwide. They are safe and well-tolerated and seem to present a range of cholesterol-independent protective actions called pleiotropic effects. Indeed, several studies claim that statins act as antioxidants [19, 96], anti-inflammatory agents [97], and can increase stability of the atherosclerotic plaque [98], improve endothelial function [99], and induce cancer cell death [100].

statins lipophilicity [100, 110–112]. In this regard, literature reports suggest that the mevalonate pathway inhibition is associated with anti-proliferative, pro-apoptotic, and anti-metastatic statins effects [113]. In addition, statins may impair cell membrane function, due to the lowering of cholesterol levels and inhibition of the tumor cell cycle, and may lead to cell death by distinct pathways, including the mitochondrial pathway (for more details, see Ref. [114] and other reviews).

Mitochondrial Oxidative Stress and Calcium-Dependent Permeability Transition are Key Players…

http://dx.doi.org/10.5772/intechopen.71610

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Prostate cancer is one of the most commonly diagnosed cancer in men and is a significant cause of male morbidity and mortality [115]. Literature reports have shown that statins protect against prostate cancer in human patients [116, 117], and some of these effects may be attributed to a decreased isoprenoid synthesis due to mevalonate pathway inhibition. As a consequence, Ras proteins that regulate signaling pathways of cell proliferation, angiogenesis, and metastasis are not able to be isoprenylated, thus reducing their function and triggering apoptosis [118]. Statins also stimulate the mitochondrial apoptosis pathway [119, 120] via an increase in pro- and decrease in anti-apoptotic Bcl-2 proteins [121], activation of caspases 3, 7, 8, and 9 [122–124], and decrease in the formation of lipid rafts, membrane microdomains involved in several regulatory functions, including cell survival [125, 126]. In addition, statins have a dose-dependent effect on cell death. For instance, simvastatin at concentrations below 10 μM induced PC3 prostate cancer cells apoptosis [21] via a mechanism sensitive to mevalonate but not to cyclosporin A (CysA), an MPT inhibitor. On the other hand, necrosis is stimulated by higher doses of simvastatin (≥60 μM) and is preceded by an increase in free cytosolic Ca2+ concentration and PTP opening, sensitive to CysA, but not to mevalonate [21]. Both MPT and necrosis induced by simvastatin (60 μM) are sensitive to L-carnitine (antioxidant) and piracetam (membrane stabilizer) in an additive manner. When combined, these compounds act at lower doses than when each compound is used separately [22]. These data provide evidence that statin toxicity to tumor cells is not only the result of HMG-CoA reductase inhibition but also is mediated by the increase in free cytosolic Ca2+ concentration, stimulation of ROS generation, and PTP opening [21, 22]. Although many studies show that statins which are efficient in inducing tumor cell death claim their potential use as adjuvant therapy, there are no robust data that non-tumor cells are less affected by statins' toxic effects than tumor cells. Therefore, it is still premature to conclude that statins are anti-tumorigenic

After decades of statins' use, some side effects have been consistently described in a minority of patients, particularly regarding muscle function. Adverse effects other than muscle symptoms such as headache, digestive problems, liver enzymes abnormalities, and neurological dysfunction may occur in some patients [127, 128]. The side effects are often the decisive factor for the noncompliance to statins treatment [129, 130] and its discontinuation usually

The precise mechanisms involved in statins toxicity and the reasons why only a few subjects are affected remain unclear. Several groups, including ours, have proposed that mitochondria

agent.

**3. Statins adverse effects**

makes the side effect symptoms disappear [131].

are the main players in statin-induced toxicity.
