Dihydroartemisinin enhances Apo2L/TRAIL-mediated apoptosis in pancreatic cancer cells via ROS-mediated up-regulation of death receptor 5.

Rui Kong,Shuang-Jia Wang,Hong-Chi Jiang,Yue Gao,Bei Sun,Ming Mu,Guang Jia,Yong-Wei Wang,De-Li Dong,Shang-Ha Pan,Zhuo-Xin Cheng

doi:10.1371/journal.pone.0037222

Rui Kong, Shuang-Jia Wang + Show 9 more

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https://doi.org/10.1371/journal.pone.0037222

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Abstract

BackgroundDihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, has recently shown antitumor activity in various cancer cells. Apo2 ligand or tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) is regarded as a promising anticancer agent, but chemoresistance affects its efficacy as a treatment strategy. Apoptosis induced by the combination of DHA and Apo2L/TRAIL has not been well documented, and the mechanisms involved remain unclear.Methodology/Principal FindingsHere, we report that DHA enhances the efficacy of Apo2L/TRAIL for the treatment of pancreatic cancer. We found that combined therapy using DHA and Apo2L/TRAIL significantly enhanced apoptosis in BxPC-3 and PANC-1 cells compared with single-agent treatment in vitro. The effect of DHA was mediated through the generation of reactive oxygen species, the induction of death receptor 5 (DR5) and the modulation of apoptosis-related proteins. However, N-acetyl cysteine significantly reduced the enhanced apoptosis observed with the combination of DHA and Apo2L/TRAIL. In addition, knockdown of DR5 by small interfering RNA also significantly reduced the amount of apoptosis induced by DHA and Apo2L/TRAIL.Conclusions/SignificanceThese results suggest that DHA enhances Apo2L/TRAIL-mediated apoptosis in human pancreatic cancer cells through reactive oxygen species-mediated up-regulation of DR5.

Highlights

Pancreatic cancer is one of the most lethal digestive system malignancies and has a very poor prognosis [1,2]
Conclusions/Significance: These results suggest that DHA enhances Apo2L/TRAIL-mediated apoptosis in human pancreatic cancer cells through reactive oxygen species-mediated up-regulation of death receptor 5 (DR5)
To determine whether DHA and Apo2L/TRAIL act synergistically to inhibit the growth of pancreatic cancer cells, we measured cell viability in BxPC-3 and PANC-1 cell lines in response to different treatment regimens

Summary

Introduction

Pancreatic cancer is one of the most lethal digestive system malignancies and has a very poor prognosis [1,2]. An effective treatment strategy for pancreatic cancer is urgently needed. It has been demonstrated that DHA effectively kills various types of cancer cells [8,9,10,11,12,13]. We have determined that DHA can significantly inhibit cell growth and induce the apoptosis of pancreatic cancer cells in a dose- and time-dependent manner but is essentially non-toxic to normal cells [9]. Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, has recently shown antitumor activity in various cancer cells. Apo ligand or tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) is regarded as a promising anticancer agent, but chemoresistance affects its efficacy as a treatment strategy. Apoptosis induced by the combination of DHA and Apo2L/TRAIL has not been well documented, and the mechanisms involved remain unclear

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