Methyl 2-cyano-3,11-dioxo-18beta-olean-1,12-diene-30-oate (beta-CDODA-Me) is a synthetic analog of the naturally occurring triterpenoid glycyrrhetinic acid, which contains a 2-cyano substituent in the A-ring. beta-CDODA-Me was a potent inhibitor of LNCaP prostate cancer cell growth (IC(50) approximately 1 muM) and activated peroxisome proliferator-activated receptor gamma (PPARgamma), whereas analogs without the cyano group were weakly cytotoxic and did not activate PPARgamma. beta-CDODA-Me induced p21 and p27, down-regulated cyclin D1 protein expression, and induced two other proapoptotic proteins, namely nonsteroidal anti-inflammatory drug-activated gene-1 and activating transcription factor-3. However, induction of these responses by beta-CDODA-Me was PPARgamma-independent and due to activation of phosphatidylinositol-3-kinase, mitogen-activated protein kinase, and jun N-terminal kinase pathways by this compound. In contrast, beta-CDODA-Me also decreased androgen receptor (AR) and prostate-specific antigen (PSA) mRNA and protein levels through kinase-independent pathways. beta-CDODA-Me repressed AR mRNA transcription, whereas decreased PSA mRNA levels were dependent on protein synthesis and were reversed by cycloheximide. Thus, potent inhibition of LNCaP cell survival by beta-CDODA-Me is due to PPARgamma-independent activation of multiple pathways that selectively activate growth-inhibitory and proapoptotic responses.
"Troglitazone increases expression of nucleobindin 2 (NUCB2) via activation of Erk in HTB185 brain medulloblastoma cells . Also, Papineni et al. demonstrated blocking Erk via the MEK inhibitor PD98059 reduced the ability of the non-TZD PPARγ ligand β-CDODA-Me to increase p21 in LNCaP prostate cancer cells . Therefore, in some situations Erk does play a role in the regulation of protein expression by TZDs and other PPARγ ligands. "
[Show abstract][Hide abstract] ABSTRACT: Thiazolidinediones (TZDs) dramatically reduce the growth of human prostate cancer cells in vitro and in vivo. To determine whether the antitumor effects of TZDs were due in part to changes in the MEK/Erk signaling pathway, we examined the regulation of Erk phosphorylation by the TZD troglitazone within the PC-3 and C4-2 human prostate cancer cell lines. Western blot analysis revealed troglitazone-induced phosphorylation of Erk in both PC-3 and C4-2 cells. Troglitazone-induced increases in Erk phosphorylation were suppressed by the MEK inhibitor U0126 but not by the PPARγ antagonist GW9662. Pretreatment with U0126 did not alter the ability of troglitazone to regulate expression of two proteins that control cell cycle, p21, and c-Myc. Troglitazone was also still effective at reducing PC-3 proliferation in the presence of U0126. Therefore, our data suggest that troglitazone-induced Erk phosphorylation does not significantly contribute to the antiproliferative effect of troglitazone.
PPAR Research 02/2012; 2012(5):929052. DOI:10.1155/2012/929052 · 1.64 Impact Factor
"Based on our results, the dual inhibition of the VEGF-A/VEGFR2 and mTOR signal pathways of CDODA-Me would lead cooperative antiangiogenic effects through inhibition of initiation and further critical stages of blood vessel formation. In addition , previous studies show that CDODA-Me decreased expression of Sp transcription factors and Sp-dependent proangiogenic genes (Papineni et al., 2008) by repression of microRNA-27a and induction of ZBTB10 (Chintharlapalli et al., 2009). Through targeting different pathways in both endothelial cells and cancer cells, CDODA-Me blocks interactions of tumors with surrounding stromal cells, thus inhibiting both tumor angiogenesis and tumor growth. "
[Show abstract][Hide abstract] ABSTRACT: Methyl 2-cyano-3,11-dioxo-18-olean-1,12-dien-30-oate (CDODA-Me), a triterpenoid acid derived synthetically from glycyrrhetinic acid, has been characterized as a peroxisome proliferator-activated receptor γ agonist with a broad range of receptor-dependent and -independent anticancer activities. Although CDODA-Me decreases the expression of some angiogenic genes in cancer cells, the direct effects of this compound on angiogenesis have not been defined. In this study, we have extensively investigated the activities of CDODA-Me in multiple angiogenesis assays. Our results showed that this agent inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration, invasion, and lamellipodium and capillary-like structure formation of human umbilical endothelial cells (HUVECs) in a concentration-dependent manner. Moreover, CDODA-Me abrogated VEGF-induced sprouting of microvessels from rat aortic rings ex vivo and inhibited the generation of new vasculature in the Matrigel plugs in vivo, where CDODA-Me significantly decreased the number of infiltrating von Willebrand factor-positive endothelial cells. To understand the molecular basis of this antiangiogenic activity, we examined the signaling pathways in CDODA-Me-treated HUVECs. Our results showed that CDODA-Me significantly suppressed the activation of VEGF receptor 2 (VEGFR2) and interfered with the mammalian target of rapamycin (mTOR) signaling, including mTOR kinase and its downstream ribosomal S6 kinase (S6K), but had little effect on the activities of extracellular signal-regulated protein kinase and AKT. Taken together, CDODA-Me blocks several key steps of angiogenesis by inhibiting VEGF/VEGFR2 and mTOR/S6K signaling pathways, making the compound a promising agent for the treatment of cancer and angiogenesis-related pathologies.
Journal of Pharmacology and Experimental Therapeutics 10/2010; 335(1):172-9. DOI:10.1124/jpet.110.171066 · 3.97 Impact Factor
"For example, in pancreatic cancer cells, CDDO-Im inhibits cell growth and induces apoptosis, and this is associated with decreased MMP and mitochondrial glutathione (GSH) and induction of reactive oxygen species (ROS) (Samudio et al., 2005). Studies in this laboratory have characterized the anticancer activity of 2-cyano-3,11-dioxo-18␤-olean-1,12-dien-30-oic acid (CDODA) and its methyl ester (CDODA-Me), which are structurally similar to CDDO and CDDO-Me but are derived from the triterpenoid glycyrrhetinic acid, a bioactive component of licorice (Chintharlapalli et al., 2007a, 2009; Chadalapaka et al., 2008b; Papineni et al., 2008; Jutooru et al., 2009). A recent study reported that one of the underlying mechanisms of action of CDODA-Me in colon cancer cells was due to the down-regulation of specificity protein (Sp) transcription factors Sp1, Sp3, and Sp4 and Sp-dependent genes (Chintharlapalli et al., 2009). "
[Show abstract][Hide abstract] ABSTRACT: The anticancer agent 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and its methyl ester (CDDO-Me) typically induce a broad spectrum of growth-inhibitory, proapoptotic, and antiangiogenic responses. Treatment of Panc1, Panc28, and L3.6pL pancreatic cancer cells with low micromolar concentrations of CDDO or CDDO-Me resulted in growth inhibition, induction of apoptosis, and down-regulation of cyclin D1, survivin, vascular endothelial growth factor (VEGF), and its receptor (VEGFR2). RNA interference studies indicate that these repressed genes are regulated by specificity protein (Sp) transcription factors Sp1, Sp3, and Sp4, and Western blot analysis of lysates from pancreatic cancer cells treated with CDDO and CDDO-Me shows for the first time that both compounds decreased the expression of Sp1, Sp3, and Sp4. Moreover, CDDO-Me (7.5 mg/kg/day) also inhibited pancreatic human L3.6pL tumor growth and down-regulated Sp1, Sp3, and Sp4 in tumors using an orthotopic pancreatic cancer model. CDDO-Me also induced reactive oxygen species (ROS) and decreased mitochondrial membrane potential (MMP) in Panc1 and L3.6pL cells, and cotreatment with antioxidants (glutathione and dithiothreitol) blocked the formation of ROS, reversed the loss of MMP, and inhibited down-regulation of Sp1, Sp3, and Sp4. Repression of Sp and Sp-dependent genes by CDDO-Me was due to the down-regulation of microRNA-27a and induction of zinc finger and BTB domain containing 10 (ZBTB10), an Sp repressor, and these responses were also reversed by antioxidants. Thus, the anticancer activity of CDDO-Me is due, in part, to activation of ROS, which in turn targets the microRNA-27a:ZBTB10-Sp transcription factor axis. This results in decreased expression of Sp-regulated genes, growth inhibition, induction of apoptosis, and antiangiogenic responses.
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