RT Journal Article
SR Electronic
T1 Methyl 2-Cyano-3,11-dioxo-18β-olean-1,12-dien-30-oate Is a Peroxisome Proliferator-Activated Receptor-γ Agonist That Induces Receptor-Independent Apoptosis in LNCaP Prostate Cancer Cells
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 553
OP 565
DO 10.1124/mol.107.041285
VO 73
IS 2
A1 Papineni, Sabitha
A1 Chintharlapalli, Sudhakar
A1 Safe, Stephen
YR 2008
UL http://molpharm.aspetjournals.org/content/73/2/553.abstract
AB Methyl 2-cyano-3,11-dioxo-18β-olean-1,12-diene-30-oate (β-CDODA-Me) is a synthetic analog of the naturally occurring triterpenoid glycyrrhetinic acid, which contains a 2-cyano substituent in the A-ring. β-CDODA-Me was a potent inhibitor of LNCaP prostate cancer cell growth (IC50 ∼1 μM) and activated peroxisome proliferator-activated receptor γ (PPARγ), whereas analogs without the cyano group were weakly cytotoxic and did not activate PPARγ. β-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 β-CDODA-Me was PPARγ-independent and due to activation of phosphatidylinositol-3-kinase, mitogen-activated protein kinase, and jun N-terminal kinase pathways by this compound. In contrast, β-CDODA-Me also decreased androgen receptor (AR) and prostate-specific antigen (PSA) mRNA and protein levels through kinase-independent pathways. β-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 β-CDODA-Me is due to PPARγ-independent activation of multiple pathways that selectively activate growth-inhibitory and proapoptotic responses. The American Society for Pharmacology and Experimental Therapeutics