Methyl 2-cyano-3,11-dioxo-18?-olean-1,12-dien-30-oate (?-CDODA-Me) and methyl 2-cyano-3,11-dioxo-18?-olean-1,12-dien-30-oate (?-CDODA-Me ) isomers are synthetic analogs of the naturally occurring triterpenoid glycyrrhetinic acid. The activity of these compounds as selective peroxisome proliferator-activated receptor ? (PPAR?) agonists and as cytotoxic anticancer agents has been investigated in colon, prostate and pancreatic cancer cells. In colon cancer cells ?-CDODA-Me arrested the growth at G2/M and this was accompanied by decreased expression of Sp1, Sp3 and Sp4 protein and mRNA and several Sp-dependent genes including survivin, vascular endothelial growth factor (VEGF), and VEGF receptor 1 (VEGFR1 or Flt-1). ?-CDODA-Me also inhibited tumor growth in athymic nude mice bearing RKO cells as xenografts. ?- CDODA-Me decreased expression of microRNA-27a (miR-27a), and this was accompanied by increased expression of two miR-27a-regulated mRNAs, namely ZBTB10 (an Sp repressor) and Myt-1 which catalyzes phosphorylation of cdc2 to inhibit progression of cells through G2/M. In LNCaP prostate cancer cells induction of two proapoptotic proteins namely nonsteroidal anti-inflammatory drug- activated gene-1 (NAG-1) and activating transcription factor-3 (ATF-3) was PPAR? independent and required activation of kinases. ?-CDODA-Me also decreased the levels of androgen receptor (AR) and prostate-specific antigen (PSA) mRNA and protein levels. Thus the cytotoxicity of ?- CDODA-Me involved multiple pathways that selectively activate growth inhibitory and proapoptotic responses. Betulinic acid (BA), an inhibitor of melanoma is a pentacyclic triterpenoid natural product that induces apoptosis and antiangiogenic responses in tumors derived from multiple tissues. However, the underlying mechanism of action of BA is unknown. In LNCaP prostate cancer cells, BA acts as a novel anticancer agent by inducing proteasome-dependent repression of Sp proteins and Sp- dependent genes. The anticancer activity of the 2-cyano substituted analogs of BA, CN-BA and its methyl ester, CN-BA-Me was also investigated in colon and pancreatic cancer cells. Both CNBA and CN-BA-Me were highly cytotoxic and activated PPAR? and induced several receptor-mediated responses. The results clearly demonstrated that both the PPAR? agonist activities of CN-BA and CN-BA-Me were structure-, response-/gene- and cell context-dependent suggesting that these compounds are a novel class of selective PPAR? modulators with potential for clinical treatment of prostate, colon and pancreatic cancer.
