Department of General Surgery, Henry Ford Health System, Detroit, MI 48202, USA.
Molecules. 2013 Mar 13;18(3):3250-65. doi: 10.3390/molecules18033250.
Methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me) is a synthetic derivative of oleanolic acid, a triterpene, with apoptosis-inducing activity in a wide range of cancer cells. Induction of apoptosis by CDDO-Me is associated with the generation of reactive oxygen species (ROS) and inhibition of telomerase activity. In the present study, we investigated the role of ROS in inhibition of telomerase by CDDO-me. Treatment of MiaPaCa-2 and Panc-1 pancreatic cancer cell lines with CDDO-Me induced the production of hydrogen peroxide and superoxide anions and inhibited the telomerase activity. Pretreatment of cells with N-acetylcycsteine, a general purpose antioxidant or overexpression of glutathione peroxidase (GPx) or superoxide dismutase-1 (SOD-1) blocked the telomerase inhibitory activity of CDDO-Me. Furthermore, blocking ROS generation also prevented the inhibition of hTERT gene expression, hTERT protein production and expression of a number of hTERT-regulatory proteins by CDDO-Me (e.g., c-Myc, Sp1, NF-κB and p-Akt). Data also showed that Akt plays an important role in the activation of telomerase activity. Together, these data suggest that inhibition of telomerase activity by CDDO-Me is mediated through a ROS-dependent mechanism; however, more work is needed to fully understand the role of ROS in down-regulation of hTERT gene and hTERT-regulatory proteins by CDDO-Me.
2-氰基-3,12-二氧代齐墩果酸甲酯（CDDO-Me）是齐墩果酸的一种合成衍生物，具有诱导多种癌细胞凋亡的活性。CDDO-Me 诱导细胞凋亡与活性氧（ROS）的产生和端粒酶活性的抑制有关。在本研究中，我们研究了 ROS 在 CDDO-Me 抑制端粒酶中的作用。用 CDDO-Me 处理 MiaPaCa-2 和 Panc-1 胰腺癌细胞系可诱导过氧化氢和超氧阴离子的产生，并抑制端粒酶活性。用 N-乙酰半胱氨酸（一种通用抗氧化剂）预处理细胞或过表达谷胱甘肽过氧化物酶（GPx）或超氧化物歧化酶-1（SOD-1）可阻断 CDDO-Me 的端粒酶抑制活性。此外，阻断 ROS 的产生也可防止 CDDO-Me 抑制 hTERT 基因表达、hTERT 蛋白产生以及 hTERT 调节蛋白（如 c-Myc、Sp1、NF-κB 和 p-Akt）的表达。数据还表明 Akt 在端粒酶活性的激活中起重要作用。综上所述，CDDO-Me 通过 ROS 依赖的机制抑制端粒酶活性；然而，仍需要进一步研究以充分了解 ROS 在 CDDO-Me 下调 hTERT 基因和 hTERT 调节蛋白中的作用。
