Dihydroartemisinin upregulates death receptor 5 expression and cooperates with TRAIL to induce apoptosis in human prostate cancer cells.
Dihydroartemisinin (DHA) is a derivative of artemisinin and is an effective anti-malaria therapeutic used worldwide. In this paper, we report that DHA is as a potential anticancer drug for prostate cancer. Our data indicate that DHA suppresses the PI3-K/Akt and ERK cell survival pathways and triggers the induction of death receptor DR5 and activation of extrinsic and intrinsic cell death signaling. DHA-mediated DR5 induction appears to occur via increased transcriptional activity of DR5 promoter. Our data also show that, while DHA has strong cytotoxicity in tumor cells, it exhibits minimal cytotoxic effects on normal prostate epithelial cells. Our studies also demonstrate that DHA worked cooperatively with death ligand TRAIL. Combination of DHA and TRAIL significantly enhanced cell killing above that noted with a single agent alone. Based on these results, we propose a novel idea of developing DHA alone and/or in combination with TRAIL for the treatment of prostate cancer.
He
Qin
Q
Department of Pharmacology, State University of New York, Upstate Medical University, Syracuse, NY, USA.
Shi
Jinxue
J
Shen
Xiao-Ling
XL
An
Jie
J
Sun
Hong
H
Wang
Lu
L
Hu
Ying-Jie
YJ
Sun
Qing
Q
Fu
Lin-Chun
LC
Sheikh
M Saeed
MS
Huang
Ying
Y
D017209:Apoptosis / Q000187:drug effects*; D037621:Artemisinins / Q000737:chemistry / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008297:Male; D008954:Models, Biological; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*
D037621:Artemisinins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C039060:artenimol; D020169:Caspases