*3.2.2 Pleiotropic effects of statins in mesenchymal tumors*

Cholesterol is involved in the sarcomagenesis process, with an inverse relationship between increased cholesterol synthesis activity and decreased survival of patients with sarcoma [11, 55].


### **Table 2.**

*Pleiotropic effects of statin on mesenchymal tumors.*

## *3.2.2.1 Effects of statins on cell proliferation and cell cycle*

Statins, essentially lipophilic ones [56], suppress cell proliferation [57], promote cell differentiation *in vitro* [56], mainly in tumor cells [56], and prevent the prenylation of Ras and Rho. These effects are due to the increased phosphorylation of IF2α, JNK and c-Jun, and alteration of the p53, p21Cip1 and CDK1 gene expression [58, 59], which arrest cells in the G0/G1 and the S phases.

## *3.2.2.2 Effect of statins on cell viability and apoptosis*

Statin induces loss of cell viability [56, 60] and anoikis [61, 62], followed by p53 translocation, cytochrome c release [63], decreased expression of bcl-2 [64], caspase 9 and 3 activation [65], apoptosis and cell differentiation [66].

## *3.2.2.3 Enhancement of chemotherapeutic effect*

Statins enhance the antitumor effects of chemotherapy [67]. Thus, lovastatin enhances the effect of doxorubicin on NIH-3 T3 sarcoma cells [65], and in osteosarcomas, stimulates apoptosis and invasive behavior [68]. Sublethal doses of simvastatin potentiate the cytotoxicity of doxorubicin in rhabdomyosarcomas [65], reducing *in vivo* cardiac toxicity in mice [69, 70]. It is believed that these effects are produced by the action of the p53 protein (**Figure 5**); the JNK phosphorylation [67]; the decreased MMP-2 activity [68], the decrease in drug resistance regulated by the p-glycoprotein/ ABCB1 gene [71], whose expression is associated with a poor prognosis in children diagnosed with soft tissue sarcoma [62].
