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Abstract
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.
Highlights
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
We have demonstrated that the antiproliferative and apoptosis inducing activity of CDDO-Me in prostate and pancreatic cancer cell lines is mediated through the inhibition of anti-apoptotic Akt/NF-κB/
We have recently shown that inhibition of cell proliferation and induction of apoptosis by CDDO-Me in pancreatic cancer cells is associated with the repression of hTERT expression, the gene that codes for telomerase, and telomerase activity [11]
Summary
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. Data 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; 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-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) and its C-28 methyl ester (CDDO-Me) and C-28 imidazole (CDDO-Im) are synthetic derivatives of oleanolic acid (OA) with several-fold greater anti-inflammatory activity than OA [1]. We have demonstrated that the antiproliferative and apoptosis inducing activity of CDDO-Me in prostate and pancreatic cancer cell lines is mediated through the inhibition of anti-apoptotic (prosurvival) Akt/NF-κB/. MTOR signaling pathways [7,8] These studies revealed that generation of reactive oxygen species (ROS) is involved in the antiproliferative and apoptosis-inducing activity of CDDO-Me [9,10]
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