Prueba de validez facial

All statin drugs are competitive inhibitors of the enzyme HMGCR. Statins bind to a portion of the HMGCR catalytic domain, which inhibits binding of the natural substrate HMG-CoA530,558. Statins

85

bind the active site of HMGCR with a 100-1000 fold higher affinity than HMG-CoA559. Importantly, while all statins share the same pharmacophore (Figure 10), the structural characteristics guide their binding affinity to HMGCR560. The mean inhibitory concentration (Ki) of the FDA approved statins and the affinity of HMG-CoA for HMGCR are given in Table 14559,561,562.

Table 11. Affinity of HMG-CoA and statins for HMGCR

Molecule HMG-CoA Atorva Fluva Lova Pitava Prava Rosuva Simva

Kd or Ki (nM) 6600 15.2 17.9 2.7 – 11.1 6.8 55.1 12 18.1

The affinity (Kd) or mean inhibitory concentration (Ki) of HMG-CoA and statins, respectively, for HMGCR. The

statin prefixes are used instead of the whole name (e.g. Atorva = Atorvastatin). Affinity and mean inhibitory concentration values are reported in nanomolar (nM)559,561,562_.

Statins dramatically reduce flux through the cholesterol biosynthesis pathway by their inhibition of the rate limiting enzymatic step, catalyzed by HMGCR563_{. The most significant steps} and branch points of the cholesterol biosynthesis pathway are shown in Figure 11. The most biologically relevant molecules affected by inhibition of HMGCR are downstream of mevalonate – cholesterol, farnesyl pyrophosphate (FPP), and geranylgeranyl pyrophosphate (GGPP). The mechanisms of action of statin therapy, both in cardiovascular disease and other diseases, are related to reductions in each of these three compounds. Before describing how statins affect cancer growth (Section 2.6, “Statin Usage in Cancer”), it is important to first describe the mechanisms of action by which statins lower cardiovascular disease risk and mortality.

86

Figure 8. The cholesterol biosynthesis pathway

Statins block HMG-CoA reductase (HMGCR, shown in blue) to shut down the cholesterol biosynthetic pathway. Other inhibitors of this pathway are shown in red. In addition to cholesterol, other downstream mediators are

87 2.2.1 Effects of Statins on Lipid Homeostasis

One of the main mechanisms of action of statin therapy is the reduction in circulating lipids, most specifically cholesterol in the form of low density lipoprotein (LDL) particles564. Statins accomplish this by acting selectively in the liver, the primary site of cholesterol biosynthesis565, largely due in part to first pass metabolism. Statins enter hepatocytes by diffusion or active transport (see “Pharmacokinetics”)530. Statin binding to HMGCR prevents it from converting HMG-CoA into mevalonate, which reduces the intracellular cholesterol concentration566_{. When} cells are deprived of cholesterol, the transport protein SREBP cleavage-activating protein (SCAP) shuttles sterol regulatory element-binding protein 2 (SREBP-2) from the ER to the Golgi, where Site-1 Protease (S1P) and Site-2 Protease (S2P) reside567. These two proteases subsequently cleave SREBP-2 into its N-terminal active form, which translocates into the nucleus and binds sterol response elements (SREs) to enhance transcription of several target genes, including HMGCR, Fatty Acid Synthase (FAS), LDL Receptor (LDLR), and Proprotein Convertase Subtiliskin/Kexin Type 9 (PCSK9)567–569. Increased expression of LDLR facilitates uptake of LDL particles into hepatocytes, which reduces blood cholesterol570. Conversely, PCSK9 acts as a negative regulator of LDLR and is negatively regulated by circulating LDL569,571,572. In short, statins both reduce new cholesterol synthesis and enhance hepatic uptake of existing, circulating cholesterol. Moreover, statin-mediated hepatic uptake of LDL particles also reduces circulating triglyceride levels in patients with hypertriglyceridemia573.

Statin treatment also affects other aspects of lipid homeostasis. Even in patients with dysfunctional LDLRs, statins decrease LDL by inhibiting synthesis of apolipoprotein B100, an essential protein for the formation of LDL particles574_{. Additionally, statins enhance circulating} levels of high density lipoprotein (HDL), which plays an important role in removing cholesterol

88

from peripheral tissues and returning it to the liver575. The increase in HDL is thought to be due to inhibition of Cholesterol Ester Transfer Protein (CETP) function, which normally acts to return cholesterol esters to LDL particles575,576. Finally, statins can lessen the oxidation of LDL particles and decrease their uptake by macrophages through regulation of scavenger receptor expression577.

2.2.2 Effects on Cardiovascular Pathobiology

In addition to modifying lipid homeostasis, statins exert pleotropic effects on other aspects of cardiovascular pathobiology. Cell-mediated effects stem from reductions in cellular signaling from small G-proteins through reducing the availability of FPP and GGPP564. In endothelial cells, decreased activation of Rho enhances expression of endothelial nitric oxide synthase (eNOS), which protects endothelial function and impedes cardiovascular disease progression578. In smooth muscle cells, reduction of Ras and Rho signaling reduces their proliferation and migration, which decreases the intimal hyperplasia associated with vascular injury579,580_{. In inflammatory cells,} statins act to decrease their proliferation and secretion of proinflammatory cytokines, such as IL- 6, IL-8, and MCP-1581,582. Finally, in myocardial cells, statins can reduce cardiac remodeling through suppression of Ras and Rac1583.

In comparison, additional benefits of statins in cardiovascular disease involve inhibition of disease progression. Acute coronary syndromes are the result of rupture of an unstable plaque in the vessel wall, which induces thrombosis and subsequent occlusion of blood flow. Statins can modify the composition of plaques, reducing the concentration of lipids, increasing collagen deposition, and decreasing metalloproteinase activity584. Statins also impede thrombosis by inhibiting platelet activation and the coagulation cascade, in part through reductions in Na+/H+

89

antiporter activity and tissue factor expression respectively585,586. Finally, statins can facilitate dissolution of thromboses by upregulation of tissue plasminogen activator (tPA)587_.