Number 3 People's Hospital, Affiliated to Shanghai Jiao-Tong University School of Medicine, Shanghai 201900, PR China.
Int J Mol Med. 2012 Apr;29(4):649-55. doi: 10.3892/ijmm.2012.895. Epub 2012 Jan 24.
We recently demonstrated that oridonin could induce apoptosis and senescence of colon cancer cells in vitro and in vivo. However, the underlying mechanism remains unknown. In this study, the involvement of reactive oxygen species in oridonin-induced cell death and senescence was investigated in colon adenocarcinoma-derived SW1116 cells. Oridonin increased intracellular hydrogen peroxide levels and reduced the glutathione content in a dose-dependent manner. N-acetylcysteine, a reactive oxygen species scavenger, not only blocked the oridonin-induced increase in hydrogen peroxide and glutathione depletion, but also blocked apoptosis and senescence induced by oridonin, as evidenced by the decrease in Annexin V and senescence-associated β-galactosidase- positive cells and the inhibition of oridonin-induced upregulation of p53 and p16 and downregulation of c-Myc. Moreover, exogenous catalase could inhibit the increase in hydrogen peroxide and apoptosis induced by oridonin, but not the glutathione depletion and senescence. Furthermore, thioredoxin reductase (TrxR) activity was reduced by oridonin in vitro and in cells, which may cause the increase in hydrogen peroxide. In conclusion, the increase in hydrogen peroxide and glutathione depletion account for oridonin-induced apoptosis and senescence in colorectal cancer cells, and TrxR inhibition is involved in this process. Given the importance of TrxR as a novel cancer target in colon cancer, oridonin would be a promising clinical candidate. The mechanism of oridonin-induced inhibition of TrxR warrants further investigation.
我们最近证明了冬凌草甲素可以在体外和体内诱导结肠癌细胞凋亡和衰老。然而，其潜在机制尚不清楚。在这项研究中，我们研究了活性氧物种在冬凌草甲素诱导的结肠腺癌细胞死亡和衰老中的作用。冬凌草甲素呈剂量依赖性地增加细胞内过氧化氢水平并降低谷胱甘肽含量。N-乙酰半胱氨酸，一种活性氧清除剂，不仅阻断了冬凌草甲素诱导的过氧化氢增加和谷胱甘肽耗竭，还阻断了冬凌草甲素诱导的细胞凋亡和衰老，这表现在 Annexin V 和衰老相关的β-半乳糖苷酶阳性细胞减少，以及冬凌草甲素诱导的 p53 和 p16 上调和 c-Myc 下调受到抑制。此外，外源性过氧化氢酶可以抑制冬凌草甲素诱导的过氧化氢增加和凋亡，但不能抑制谷胱甘肽耗竭和衰老。此外，冬凌草甲素在体外和细胞中降低了硫氧还蛋白还原酶（TrxR）的活性，这可能导致过氧化氢的增加。总之，过氧化氢的增加和谷胱甘肽的耗竭导致了大肠癌细胞中冬凌草甲素诱导的细胞凋亡和衰老，而 TrxR 的抑制参与了这一过程。鉴于 TrxR 在结肠癌中作为一种新型癌症靶点的重要性，冬凌草甲素将是一种很有前途的临床候选药物。冬凌草甲素诱导 TrxR 抑制的机制值得进一步研究。
