Erxi Wu, assistant professor of pharmaceutical sciences, recently co-wrote two papers on the natural polyphenol resveratrol, trans-3,4,5-trihydroxystilbene, which has gained notoriety stemming in part from what is known as the French paradox. The paradox refers to the observation that French people are at lower risk for cardiovascular diseases compared to people in other industrialized countries despite a diet rich in saturated fats. The two papers were published in Current Medicinal Chemistry.
The first paper is on resveratrol inhibiting the epithelial-mesenchymal transition of pancreatic cancer cells via suppression of the PI-3K/Akt/NF-κB pathway. According to the authors, resveratrol, a compound in grapes, berries and peanuts, possesses a wide spectrum of pharmacologic properties, including anti-tumor metastasis activities. However, the underlying mechanisms through which resveratrol inhibits the metastasis of pancreatic cancer are still not fully understood.
As epithelial-to-mesenchymal transition is a key player for metastasis in tumors, the aim of the study was to determine whether resveratrol affects epithelial-to-mesenchymal transition in pancreatic cancer cells and the related mechanism. The results show resveratrol not only inhibits cell proliferation, migration and invasion in a dose-dependent manner, but also regulates the expression of epithelial-to-mesenchymal transition-related genes such as E-cadherin, N-cadherin and vimentin, which are important for cancer cellular motility, invasiveness and metastasis during tumorigenesis.
In addition, the levels of phospho-Akt and phospho-NF-κB in BxPC-3 and Panc-1 cells were reduced by both resveratrol and LY294002, a PI3-K inhibitor. Furthermore, transforming growth factor-β induced alterations in epithelial-to-mesenchymal transition cell morphology and increased cell invasive ability also could be reversed by resveratrol.
“Taken together, these data indicate that resveratrol suppresses pancreatic cancer migration and invasion through the inhibition of the PI-3K/Akt/NF-κB signaling pathway,” Wu said. “This study suggests that resveratrol may be a potential anticancer agent for pancreatic cancer.”
The paper was co-written with Qingyong Ma lab at Xi’an Jiaotong University, China. “Collaborating with Dr. Ma, we together would like to find better cancer therapeutics and elucidate the mechanisms of the targeted therapy for pancreatic carcinoma,” Wu said.
In the second paper, the researchers used in silico and biochemical analyses to identify quinone reductase 2 as a target of piceatannol. Piceatannol is a metabolite of resveratrol. Piceatannol also occurs naturally in food sources such as grapes, berries, peanuts and sugar cane. According to the article’s writers, led by Joseph Wu’s lab at New York Medical College, piceatannol produced inhibition comparable to resveratrol.
To determine whether quinone reductase 2 plays a role in the observed effects, in silico analysis was performed. Piceatannol interacted with quinone reductase 2 at the same site as resveratrol forming hydrogen bond with asparagine-161. Quinone reductase 2 mediated anti-prostate cancer effects of piceatannol also were tested and supported by the attenuation of anti-proliferative activity and reduction in extent of inhibition of quinone reductase 2 activity by piceatannol in quinone reductase 2 - knockdown cells relative to quinone reductase 2 expressing cells, and by the copious expression of CYP1B in CWR22Rv1 cells.
“These results show that quinone reductase 2 is an intracellular target for piceatannol, suggesting that prostate cancer prevention by resveratrol may be partially attributed to its conversion to piceatannol,” Wu said.
Current Medicinal Chemistry covers developments in medicinal chemistry and rational drug design.
Wu laboratory research interests include cancer therapeutic targets, drug target proteins, drug discovery and biomarkers. For more information about Wu’s lab, visit www.ndsu.edu/pharmsci/faculty_staff/erxi_wu/.
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