Pristimerin, a quinonemethide triterpenoid, induces apoptosis in pancreatic cancer cells through the inhibition of pro-survival Akt/NF-κB/mTOR signaling proteins and anti-apoptotic Bcl-2

Abstract

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 PKCɛ. 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.

Induction of cell cycle arrest and apoptosis by betulinic acid-rich fraction from Dillenia suffruticosa root in MCF-7 cells involved p53/p21 and mitochondrial signalling pathway

“…It was noted that the increase in Bax/Bcl-2 ratio was mainly due to the down-regulation of Bcl-2 at protein level, but not at the mRNA level. Thus, it is suggested that Bcl-2 protein is posttranslationally modified by either phosphorylation or ubiquitination via MAPKs and AKT, resulting in a proteosomal degradation of Bcl-2 protein which increases the BAX/BCL-2 ratio to initiate the mitochondrial apoptotic pathway (Deeb et al, 2014;Liu et al, 2013;Gao and Dou, 2000).…”

Ultrasound-Assisted Extraction of Pristimerin from <i>Celastrus orbiculatus</i> Using Response Surface Methodology

“…[4][5][6][7][8][9] So, the recovery of pristimerin from Celastrus orbiculatus has strong potential in pharmaceutical industry. The chemical structure of pristimerin is shown in Fig.…”

Absorption and metabolism characteristics of pristimerin as determined by a sensitive and reliable LC–MS/MS method

“…In addition, several studies have reported that pristimerin possesses potent anti-cancer effect [7][8][9][10][11][12]. The mechanism of anticancer activity of pristimerin was mainly involved in suppressing the formation of proteasomes [13], downregulation of NF-κB activity and cyclin D1 expression, and activation of Bax, caspase, and PARP-1 [9,13,14]. Therefore, pristimerin has the potential of becoming a lead compound in anti-cancer drugs.…”

“…Some research articles have found that pristimerin and its biological analog URB602 are inhibitors of monoglyceride lipase, which could help us better understand the function of monoglyceride lipase [5,6]. In addition, several studies have reported that pristimerin possesses potent anti-cancer effect [7][8][9][10][11][12]. The mechanism of anticancer activity of pristimerin was mainly involved in suppressing the formation of proteasomes [13], downregulation of NF-κB activity and cyclin D1 expression, and activation of Bax, caspase, and PARP-1 [9,13,14].…”