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


RESULTS
Here, 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
These results suggest that DHA enhances Apo2L/TRAIL-mediated apoptosis in human pancreatic cancer cells through reactive oxygen species-mediated up-regulation of DR5.
Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China.
Rui
R
Kong
Guang
G
Jia
Zhuo-xin
ZX
Cheng
Yong-wei
YW
Wang
Ming
M
Mu
Shuang-jia
SJ
Wang
Shang-ha
SH
Pan
Yue
Y
Gao
Hong-chi
HC
Jiang
De-li
DL
Dong
Bei
B
Sun
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D037621:Artemisinins / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D010190:Pancreatic Neoplasms / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*
D000970:Antineoplastic Agents; D037621:Artemisinins; D017382:Reactive Oxygen Species; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C039060:artenimol