Brucein D, a Naturally Occurring Tetracyclic Triterpene Quassinoid, Induces Apoptosis in Pancreatic Cancer through ROS-Associated PI3K/Akt Signaling Pathway.

Zheng-Quan Lai,Siu-Po Ip,Zi-Ren Su,Zhi-Xiu Lin,Jian-Hui Xie,Hui-Jun Liao,Yun-Long Chen,Po-Sing Leung,Yan-Fang Xian,Zheng Lu

doi:10.3389/fphar.2017.00936

Abstract

Brucein D (BD), a major active quassinoid in Brucea javanica, has exhibited pronounced anticancer activities. However, the biologic mechanisms have not been fully explored. In this study, BD exhibited more potent cytotoxic effect on pancreatic cancer (PanCa) cell lines, while exerted weaker cytotoxic effects on GES-1 cells (non-tumorigenic). BD was shown to elicit apoptosis through inducing both the intrinsic and extrinsic mitochondria-mediated caspase activations. Furthermore, the BD-induced apoptotic effects were dependent on the accumulated reactive oxygen species (ROS) and inactivation of PI3K/Akt signaling pathway. Pretreatment with tempol completely prevented the cellular apoptosis induced by BD, and recovered the inactivation of AKT, which suggested ROS essentially involved in BD-elicited apoptosis and down-regulation of PI3K/Akt pathway. In addition, the results obtained from orthotopic xenograft in nude mice were congruent with those of the in vitro investigations. These results support the notion that BD held good potential to be further developed into an effective pharmaceutical agent for the treatment of PanCa.

Highlights

Pancreatic cancer (PanCa) is an aggressive malignant disease usually diagnosed at an advanced stage
The results suggested that reactive oxygen species (ROS) generation was required for the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway in Brucein D (BD)-induced cellular apoptosis in human pancreatic cancer (PanCa) cells
We further investigated whether the pancreatic tumor growth inhibition by BD in our model was related to the induction of apoptosis, inactivation of PI3K/Akt and activation of mitogen-activated protein kinases (MAPKs)

Summary

Introduction

Pancreatic cancer (PanCa) is an aggressive malignant disease usually diagnosed at an advanced stage. PanCa is at present the fourth dominating cause of cancer-oriented death in the Western word. In 2016, 53,070 new cases of PanCa were expected in the United States with 41,780 deaths (Siegel et al, 2016). Radiotherapy, chemotherapy, and surgery, median life expectancy of PanCa patients post diagnosis is less than half a year and the overall 5-year survival rate is between 3 and 5% (Iovanna et al, 2012). Surgical operation is still the potential effective regime for management of this disease.

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Conclusion