Lack of effective
therapeutics for
pancreatic cancer at the present time underscores the dire need for safe and effective agents for the treatment of this
malignancy. In the present study, we have evaluated the anticancer activity and the mechanism of action of
pristimerin (PM), a quinonemethide
triterpenoid, against MiaPaCa-2 and Panc-1 pancreatic ductal
adenocarcinoma (PDA) cell lines. Treatment with PM inhibited the proliferation and induced apoptosis in both cell lines as characterized by the increased
Annexin V-binding and cleavage of PARP-1 and procaspases -3, -8 and -9. PM also induced mitochondrial depolarization and the release of
cytochrome c from the mitochondria. The induction of apoptosis by PM was associated with the inhibition of the pro-survival Akt, NF-κB and mTOR signaling
proteins and their downstream intermediaries such as Foxo-3α and
cyclin D1 (Akt); Cox-2 and
VEGF (NF-κB); p-S6K1 and p-4E-BP1 (mTOR) as well as PKCε. Treatment with PM also inhibited the expression of anti-apoptotic Bcl-2 and
survivin but not Bcl-xL. The downregulation of Bcl-2 by PM was not due to proteasomal or lysosomal proteolytic degradation of Bcl-2, since treatment with PM in the presence of proteasomal inhibitors
MG132 or
lactacystin (LAC) or
calpain inhibitor MG101 failed to block the downregulation of Bcl-2 by PM. On the other hand, RT-PCR analysis showed the inhibition of Bcl-2
mRNA by PM in a dose-related manner, indicating that inhibition of Bcl-2 by PM is mediated through the suppression of Bcl-2 gene expression. Thus, the mechanistic understanding of the antitumor activity of
pristimerin could facilitate in vivo efficacy studies of
pristimerin for
pancreatic cancer.