| dc.description.abstract | Methyl 2-cyano-3,11-dioxo-18β-olean-1,12-dien-30-oate (β-CDODA-Me) and
methyl 2-cyano-3,11-dioxo-18α-olean-1,12-dien-30-oate (α-CDODA-Me ) isomers are
synthetic analogs of the naturally occurring triterpenoid glycyrrhetinic acid. The activity
of these compounds as selective peroxisome proliferator-activated receptor γ (PPARγ)
agonists and as cytotoxic anticancer agents has been investigated in colon, prostate and
pancreatic cancer cells. In colon cancer cells β-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). β-CDODA-Me also
inhibited tumor growth in athymic nude mice bearing RKO cells as xenografts. β-
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 PPARγ independent and required activation of
kinases. β-CDODA-Me also decreased the levels of androgen receptor (AR) and
prostate-specific antigen (PSA) mRNA and protein levels. Thus the cytotoxicity of β-
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 PPARγ and induced several
receptor-mediated responses. The results clearly demonstrated that both the PPARγ
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 PPARγ
modulators with potential for clinical treatment of prostate, colon and pancreatic cancer. | en |
