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Methyl 2-Cyano-3,11-dioxo-18β-olean-1,12-dien-30-oate Is a Peroxisome Proliferator-Activated Receptor- Agonist That Induces Receptor-Independent Apoptosis in LNCaP Prostate Cancer Cells

Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas (S.P., S.S.); and Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas (S.C., S.S.)

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 (PPAR), whereas analogs without the cyano group were weakly cytotoxic and did not activate PPAR. 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 PPAR-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 PPAR-independent activation of multiple pathways that selectively activate growth-inhibitory and proapoptotic responses.

Address correspondence to: Dr. Stephen Safe, Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, College Station, TX 77843-4466. E-mail: ssafe{at}cvm.tamu.edu