**2.2 HMGCoAR inhibition by statins**

Statins inhibit the enzyme HMGCoAR, binding to the enzyme active site instead of HMGCoA [14]. There are differential effects of statins according to the specific tissue analyzed (liver *vs* non-hepatic) or polarity (hydrophilic *vs* lipophilic) [15]. The more lipophilic, the higher levels in non-hepatic tissues [16], while the hydrophilic are more hepato-selective [17].

### **2.3 Increased cholesterol needed in tumor cells**

Increased cholesterol synthesis requires a rise in HMGCoAR activity; enhanced absorption of low-density lipoprotein (LDL); and/or both mechanisms [18].

*Statins: Are Lipid-lowering Drugs Useful in Sarcomas? DOI: http://dx.doi.org/10.5772/intechopen.107127*

### **Figure 5.**

*The mevalonate (MVA) pathway in cancer progression. The MVA pathway is dysregulated in several cancer cells due to mutations or abnormal signaling of different proteins/pathways. Upregulation of MVA pathway drives increased protein prenylation thus promoting a malignant phenotype of cancer cells with uncontrolled cell invasive growth and survival. In cancer cells expressing a mutation of tumor protein p53, there is a positivefeedback loop where p53 interacts with sterol regulatory element-binding protein (SREBP), leading to increased activation of the MVA pathway activity and therefore higher levels of MVA. This MVA leads to the stabilization of p53 mutation as well as promotes protein prenylation, thus accelerating cancer progression.*

### *2.3.1 Expression of HMGCoAR in tumors*

Overexpression or activation of HMGCoAR [10] produces the isoprenoids necessary to maintain pro-tumor benefits (**Figure 5**) [19]. High levels of HMGCoAR, present in various types of tumors [20–22], are associated with favorable prognostic criteria [20], such as prolonged relapse-free survival [23, 24] or predicted response to treatment [24].

### *2.3.2 LDL receptor expression*

Physiologically, plasma cholesterol transported in LDL is internalized into the cell upon contact with its receptor. If the cell needs cholesterol, it increases its synthesis and LDL receptor activity; otherwise, both activities decrease [24]. In tumor cells, higher cholesterol requirements cause an increase in LDL receptor concentration, associated with an increased plasma LDL activity and absorption [25–27].
