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.

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.

• Authors: Sabitha Papineni, Sudhakar Chintharlapalli, Stephen Safe
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 73 Issue 2 Pg. 553-65 (Feb 2008) ISSN: 1521-0111 [Electronic] United States
• PMID: 17989348 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• PPAR gamma
• Glycyrrhetinic Acid

Topics

• Antineoplastic Agents (chemistry, pharmacology, therapeutic use)
• Apoptosis (drug effects, physiology)
• Cell Line, Tumor
• Glycyrrhetinic Acid (analogs & derivatives, pharmacology, therapeutic use)
• Humans
• Male
• PPAR gamma (agonists, metabolism)
• Prostatic Neoplasms (drug therapy, metabolism, pathology)