Synergistic anticancer effects of valproic acid, atorvastatin and pioglitazone in human malignant and murine cells

Valproic acid, atorvastatin and pioglitazone belong to different therapeutic drug classes and exhibit biological activities that are capable of interfering with cancer development. In this study, we examined the anticancer synergistic effects of these three drugs in experimental models in vitro and in vivo. Cytotoxic activity was determined against K562, NCI-H292 and HEp-2 lines cells. The Ehrlich carcinoma was used as in vivo model. Atorvastatin associated with pioglitazone, presented cytotoxicity against NCI-H292 cells with IC50 value 3.75 µg/ml. The ultra-structural analysis showed that the atorvastatin in combination with pioglitazone induced apoptosis in 66.3% of the cells. Treatment with either valproic acid or valproic acid + atorvastatin + pioglitazone presented cytotoxicity in Ehrlich carcinoma cells, with IC50 values equal to 10.8 and 11.4 µg/ml, respectively. In evaluation of antitumor effects in vivo it was observed that valproic acid or the atorvastatin + pioglitazone induced tumor inhibition of 60.2 and 64.9%, respectively. However, histopathology analysis suggests that the liver and kidneys are affected by both treatments. In conclusion, the data indicate that atorvastatin + pioglitazone present synergistic anticancer effect in lung cancer cells and solid tumours.