Methyl 2-cyano-3,11-dioxo-18 beta-olean-1,12-dien-30-oate is a peroxisome proliferator-activated receptor- gamma agonist that induces receptor-independent apoptosis in LNCaP prostate cancer cells

Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, College Station, TX 77843-4466, USA.
Molecular pharmacology (Impact Factor: 4.12). 03/2008; 73(2):553-65. DOI: 10.1124/mol.107.041285
Source: PubMed

ABSTRACT 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND AND PURPOSE: This study was performed to investigate the effects of 4-O-methylhonokiol (MH), a constituent of Magnolia officinalis, on human prostate cancer cell growth and its mechanism of action. EXPERIMENTAL APPROACH: Anti-cancer effects of MH were examined using human prostate cancer or normal cells. The effects were validated by in vivo Xenograft animal model. KEY RESULTS: Pull-down assay and molecular docking study suggested that MH may directly bind to PPAR-γ and elevate its activity. In consistent with these results, MH increased transcriptional activity of PPAR-γ, while decreased NF-κB activity. Growth inhibition of human prostate cancer cells was achieved by MH, which was blunted by PPAR-γ antagonist (GW9662). MH caused apoptotic cell death and it was related to G(0) -G(1) phase cell cycle arrest. We found that MH increased expression of the cell cycle regulator p21, and apoptotic proteins, whereas the compound decreased phosphorylation of Rb and anti-apoptotic proteins. Small interfering RNA against p21 or transfection of p21 with mutation on cyclin D1/Cdk4 binding site blocked MH-induced cell growth inhibition, and inhibition of NF-κB activity. With animal studies, MH inhibited tumor growth, NF-κB activity and expression of anti-apoptotic proteins, whereas increased transcriptional activity and expression of PPAR-γ, and the expression of apoptotic proteins as well as p21 in tumor tissues. CONCLUSIONS AND IMPLICATION: These results indicate that MH may suppress growth of human prostate cancer cells through activation of PPAR-γ, suppression of NF-κB as well as arrest of cell cycle. Thus, MH might be a useful tool for treatment of prostate cancer.
    British Journal of Pharmacology 10/2012; 168(5). DOI:10.1111/j.1476-5381.2012.02235.x · 4.99 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Fourteen of the methyl 2-cyano-3,12-dioxo-18β-olean-1,9(11)-dien-30-oate (CDODO-Me-12, ) analogues with different structures of ring C were synthesized to determine the active groups for inhibiting cell growth and inducing apoptosis in human leukemia HL-60 cells. An unsaturated group in ring C was required to maintain the ability to inhibit cell growth and induce apoptosis. Compound with 9(11),12-dien in ring C displayed comparable apoptosis induction ability to associated with decreased levels of c-FLIP, but not Mcl-1 and XIAP. Compound had decreased ability to deplete GSH compared to compound . Compound represents a new active compound acting through a different mechanism from that of compound .
    Organic & Biomolecular Chemistry 07/2014; 12(34). DOI:10.1039/c4ob00703d · 3.49 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A general method for the introduction of thiol groups at positions 1, 2, and 3 of glycyrrhetinic acid has been developed starting from a protected 2α,3α-oxido-derivative. Conversion into the corresponding 2β,3β-epithio-derivative was followed by ring-opening leading to either 2- or 3-substituted thio derivatives. Conversely, 3α-configured allylic alcohol intermediates derived from the 2,3-epoxide provided efficient access to both diastereoisomeric 3-thio derivatives as well as 1α-thio derivatives. The stereochemistry of the newly formed stereogenic centers was rigorously proven using X-ray crystallography.
    Tetrahedron 06/2010; 66(24):4390-4402. DOI:10.1016/j.tet.2010.03.098 · 2.82 Impact Factor