Pristimerin Causes G1 Arrest, Induces Apoptosis, and Enhances the Chemosensitivity to Gemcitabine in Pancreatic Cancer Cells

Abstract

Despite rapid advances in chemotherapy and surgical resection strategies, pancreatic cancer remains the fourth leading cause of cancer related deaths in the United States with a 5-year survival rate of less than 5%. Therefore, novel therapeutic agents for the prevention and treatment of pancreatic cancer are urgently needed. The aim of this study was to investigate the effect of pristimerin, a quinonemethide triterpenoid compound isolated from Celastraceae and Hippocrateaceae, on inhibition of cell proliferation and induction of apoptosis in three pancreatic cancer cells, BxPC-3, PANC-1 and AsPC-1, in both monotherapy and in combination with gemcitabine. Treatment with pristimerin decreased the cell proliferation of all three pancreatic cancer cells in a dose- and time-dependent manner. Treatment of pancreatic cancer cells with pristimerin also resulted in G1-phase arrest which was strongly associated with a marked decrease in the level of cyclins (D1 and E) and cyclin-dependent kinases (cdk2, cdk4 and cdk6 ) with concomitant induction of WAF1/p21 and KIP1/p27. Pristimerin treatment also resulted in apoptotic cell death, cleavage of caspase-3, modulation in the expressions of Bcl-2 family proteins, inhibition of the translocation and DNA-binding activity of NF-κB. In addition, pristimerin potentiated the growth inhibition and apoptosis inducing effects of gemcitabine in all three pancreatic cancer cells, at least in part, by inhibiting constitutive as well as gemcitabine-induced activation of NF-κB in both its DNA-binding activity and transcriptional activity. Taken together, these data provide the first evidence that pristimerin has strong potential for development as a novel agent against pancreatic cancer.

Mechanism of gemcitabine-induced suppression of human cholangiocellular carcinoma cell growth

“…In the gemcitabinesensitive HuCCT-1 cells, the anti-proliferative effect of gemcitabine led to G1 arrest through a reduction of cyclin d1. Although some studies have reported that gemcitabine could inhibit cell-phase transitioning during G1 phase (1,21), to date, there are no studies on cyclin d1 reduction as an anticancer effect of gemcitabine in CCC cells. This study revealed that gemcitabine induced a cell cycle arrest at the G0/G1 phase by reducing cyclin d1 levels in HuCCT-1 cells in vitro.…”

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.…”

Piperlongumine Suppresses Growth and Sensitizes Pancreatic Tumors to Gemcitabine in a Xenograft Mouse Model by Modulating the NF-kappa B Pathway

“…The NF-kB DNA-binding activity was determined using the Trans-Am NF-kB /p65 ELISA Kit following the instructions outlined by the manufacturer and as described previously (4). Briefly, nuclear and cytosolic fractions were prepared from cells by using the Nuclear Extraction Kit following the instructions outlined by the manufacturer.…”

“…In the year 2013 in the United States alone, almost 45,220 men and women were diagnosed with pancreatic cancer and 38,460 died of disease (3). The poor prognosis of pancreatic cancer is mostly due to the lack of ability for early detection, the aggressive biologic behavior of the tumor and the insensitivity to chemotherapy (4). Gemcitabine, erlotinib, and abraxane are the only FDA-approved agents to treat pancreatic cancer.…”