Abstract
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.
Footnotes
-
This work was supported by the National Institutes of Health (ES09106) and the Texas Agricultural Experiment Station.
-
S.P. and S.C. contributed equally to this study.
-
ABBREVIATIONS: PPAR, peroxisome proliferator-activated receptor; PGJ2, 15-deoxy-Δ12,14-prostaglandin J2; TZD, thiazolidinedione; CDDO, 2-cyano-3,12-dioxo-17α-olean-1,9-dien-28-oic acid; C-DIM, 1,1-bis(3′-indolyl)-1-(p-substituted phenyl)methane; GA, glycyrrhetinic acid; β-CDODA-Me, methyl 2-cyano-3,11-dioxo-18β-olean-1,12-diene-30-oate; NAG-1, nonsteroidal anti-inflammatory drug-activated gene 1; AR, androgen receptor; PSA, prostate-specific antigen; T007, N-(4′-aminopyridyl)-2-chloro-5-nitrobenzamide; DIM, 3,3′-diindolylmethane; ATF3, activating transcription factor 3; MAPK, mitogen-activated protein kinase; JNK, c-Jun NH2-terminal kinase; FBS, fetal bovine serum; DMEM, Dulbecco's modified Eagle's medium; DMSO, dimethyl sulfoxide; FACS, fluorescence-activated cell sorting; PCR, polymerase chain reaction; TBST, Tris-buffered saline/Tween 20; EGR-1, early growth response-1; PARP, poly(ADP-ribose) polymerase; DHT, dihydrotestosterone; PI3K, phosphoinositol-3-kinase; NAC, N-acetyl cysteine; PI, propidium iodide; MG132, N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal; PD98059, 2′-amino-3′-methoxyflavone; LY294002, 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride; SP600125, 1,9-pyrazoloanthrone; GF109203X, 3-[1-[3-(dimethylaminopropyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione monohydrochloride.
- Received August 28, 2007.
- Accepted November 7, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|
