LAUSR

The use of statins as a potential cancer drug has been investigated; however the molecular mechanisms involved in their anti-oxidant, anti-proliferative and anti-cancer effects remain elusive. In our study, we investigated the involvement of downstream mevalonate products that mediate the anti-oxidant and anti-proliferative effects of Atorvastatin (Ato), and its effect on microRNA-145 expression in HepG2 hepatocellular carcinoma cells. An amorphous soluble form of Ato was prepared and found to be cytotoxic in vitro [IC50 (1.2 mM); 48 h]. Atorvastatin induced a dose-dependent increase in cell mortality with a concomitant depletion of intracellular ATP levels (p = 0.005); significantly increased extracellular nitrite levels (p = 0.001) and decreased lipid peroxidation (p = 0.0097) despite a decrease in GSH. The intrinsic apoptotic pathway was activated via increased caspase -9 (p < 0.0001) and -3/7 (p = 0.0003) activities. Increased protein expression of pGSK3-(α/β) (p = 0.0338), p53 (p = 0.0032), Mdm2 (p < 0.0001), with significantly diminished levels of PI3K (p = 0.0013), pAKT (p = 0.0035), and Akt (p = 0.0077), indicated that Ato-mediated cell death occurred via inhibition of the PI3K/Akt pathway. Additionally, the expression of PI3K (p = 0.0001) and c-myc (p = 0.0127) were also downregulated, whilst and miRNA-145 (p = 0.0156) was upregulated. In conclusion our data strongly indicates a plausible mechanism involved in the cytotoxic effects of Ato and is the first study to show that Ato modulates miR-145 expression in hepatocytes. ≤ .