**5.2 Combined treatment of statins with chemotherapy**

Statins can be administered at high doses to cancer patients (i.e. 15 mg/kg/day for simvastatin; 25 mg/kg/day for lovastatin), but the expected effects have not been observed [62]. However, statins sensitize the tumor cells to the action of chemotherapy, improving antitumor efficacy, due to the synergism of these drugs, enhancing cytotoxicity [60], increasing the therapeutic window of statins, and reducing toxicity [63]. In sarcomas, statins increase the anti-tumor efficacy of doxorubicin or cisplatin on human osteo- and fibrosarcoma in an additive manner [53]. Besides, atorvastatin potentiates the effect on viability, migration, and cell invasion in human osteosarcoma cells [45]. In a xenograft model of human sarcoma, lovastatin enhances doxorubicin efficacy, reducing acute doxorubicin-induced heart damage [22, 46]. In the same model with osteosarcoma cells, simvastatin increased methotrexate cytotoxic effect, being necessary for lower doses of this drug and decreasing the toxicity

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

in the mice. Besides, increased the reduction in tumor volume caused by methotrexate and markedly decreased the rate of lung metastases [54]. In this sense, there are also some positive reports showing the efficacy of the combination of these drugs [64]. Therefore, in a patient with rhabdomyosarcoma refractory to chemotherapy, statins contributed to the improvement of the patient after receiving radiotherapy and being treated with bevacizumab [90]. However, it has also been described in other drugs that patient survival did not improve with this strategy [65].

### **5.3 Disadvantages and inappropriate effects of using statins**

Several advantages have been associated with statin therapy, but some drawbacks have also been described. For instance, the low bioavailability of statins (5%–20%) limits their effectiveness [63, 66]. For this reason, nanocarriers have been developed [67] to overcome the lower oral bioavailability of statins [66]. Another drawback of statins may be myopathies [91], due to direct effect of statins on muscle or autoimmune responses from autoantibodies against HMGCoAR [68]. Also, statins could increase the risk of developing diabetes mellitus (in 10%−20% of patients receiving statins) [69], increase of the rate of hemorrhagic stroke when blood cholesterol levels are reduced [70], or increased liver enzymes, although hepatotoxicity is rarely observed [92].
