Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8544748 | Chemico-Biological Interactions | 2018 | 26 Pages |
Abstract
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 (1.2â¯mM); 48â¯h]. Atorvastatin induced a dose-dependent increase in cell mortality with a concomitant depletion of intracellular ATP levels (pâ¯=â¯0.005); significantly increased extracellular nitrite levels (pâ¯=â¯0.001) and decreased lipid peroxidation (pâ¯=â¯0.0097) despite a decrease in GSH. The intrinsic apoptotic pathway was activated via increased caspase â9 (pâ¯<â¯0.0001) and â3/7 (pâ¯=â¯0.0003) activities. Increased protein expression of pGSK3-(α/β) (pâ¯=â¯0.0338), p53 (pâ¯=â¯0.0032), Mdm2 (pâ¯<â¯0.0001), with significantly diminished levels of PI3K (pâ¯=â¯0.0013), pAKT (pâ¯=â¯0.0035), and Akt (pâ¯=â¯0.0077), indicated that Ato-mediated cell death occurred via inhibition of the PI3K/Akt pathway. Additionally, the expression of PI3K (pâ¯=â¯0.0001) and c-myc (pâ¯=â¯0.0127) were also downregulated, whilst and miRNA-145 (pâ¯=â¯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.â¯â¤â¯
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Authors
Taskeen Fathima Docrat, Savania Nagiah, Anand Krishnan, Dhaneshree B. Naidoo, Anil A. Chuturgoon,