Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Science, University of KwaZulu-Natal, South Africa.
Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Science, University of KwaZulu-Natal, South Africa.
Chem Biol Interact. 2018 May 1;287:32-40. doi: 10.1016/j.cbi.2018.04.005. Epub 2018 Apr 6.
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 [IC (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. ≤ .
他汀类药物作为一种潜在的癌症药物已经被研究过；然而，其抗氧化、抗增殖和抗癌作用的分子机制仍不清楚。在我们的研究中，我们研究了调节阿托伐他汀（Ato）抗氧化和抗增殖作用的下游甲羟戊酸产物的参与及其对 HepG2 肝癌细胞中 microRNA-145 表达的影响。我们制备了一种无定形可溶性阿托伐他汀形式，发现其在体外具有细胞毒性[IC（1.2mM）；48h]。阿托伐他汀诱导细胞死亡率呈剂量依赖性增加，同时细胞内 ATP 水平下降（p=0.005）；显著增加细胞外亚硝酸盐水平（p=0.001），降低脂质过氧化（p=0.0097），尽管 GSH 减少。尽管 GSH 减少，但通过增加 caspase-9（p<0.0001）和 -3/7（p=0.0003）的活性，激活了内在凋亡途径。GSK3-（α/β）（p=0.0338）、p53（p=0.0032）、Mdm2（p<0.0001）的蛋白表达增加，而 PI3K（p=0.0013）、pAKT（p=0.0035）和 Akt（p=0.0077）的水平显著降低，表明 Ato 介导的细胞死亡是通过抑制 PI3K/Akt 途径发生的。此外，PI3K（p=0.0001）和 c-myc（p=0.0127）的表达也下调，而 miRNA-145（p=0.0156）上调。总之，我们的数据强烈表明 Ato 细胞毒性作用涉及一种合理的机制，并且是第一个表明 Ato 调节肝细胞中 miR-145 表达的研究。
