Growth inhibitory effects of dihydroartemisinin on pancreatic cancer cells: involvement of cell cycle arrest and inactivation of nuclear factor-kappaB.
OBJECTIVE
In a recent publication, we have shown that dihydroartemisinin (DHA), a derivative of antimalaria drug artemisinin, inhibits growth of pancreatic cancer cells in vitro and in vivo mediated by its anti-proliferative and pro-apoptotic effects. As it has been shown that the apoptosis might be induced due to cell cycle arrest, and that transcriptional factor nuclear factor-kappa B (NF-kappaB) plays vital roles in the apoptosis of pancreatic cancer cells, we extend our study to investigate the effects of DHA on cell cycle progression and NF-kappaB activity in pancreatic cancer cells to further reveal the anticancer effects of DHA on pancreatic cancer.


METHODS
Cell cycle progression was determined by propidium iodide staining and flow cytometry. Changes in the expression of cell cycle-associated proteins were detected using Western blot analysis. Measurement of NF-kappaB activity was performed with immunoblot analyzing the nuclear protein expression of NF-kappaB/p65 and ELISA detecting the NF-kappaB DNA-binding activity.


RESULTS
The treatment with DHA resulted in a dose-dependent G(0)/G(1) cell cycle arrest and regulated the expression of some cyclins, cdks and cdk inhibitors that involved in the G(0)/G(1) cell cycle progression such as cyclin E, cdk2, cdk4 and p27(Kip1) in pancreatic cancer BxPC-3 and AsPC-1 cells. The translocation and DNA-binding activity of NF-kappaB were inhibited in DHA-treated cells in a dose-dependent manner, indicated the inactivation effects of DHA in pancreatic cancer cells.


CONCLUSIONS
Together with our previous observations, our data show that DHA induces cell cycle arrest and apoptosis in pancreatic cancer cells, and this effect might be due to inhibition of NF-kappaB signaling. We suggest that DHA could be developed as a novel agent against pancreatic cancer.
Chen
Hua
H
Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, 150001 Harbin, China. chenhuahyd@yahoo.com.cn
Sun
Bei
B
Wang
Shuangjia
S
Pan
Shangha
S
Gao
Yue
Y
Bai
Xuewei
X
Xue
Dongbo
D
D000970:Antineoplastic Agents / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007399:Interphase / Q000187:drug effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014178:Translocation, Genetic / Q000187:drug effects
D000970:Antineoplastic Agents; D037621:Artemisinins; D016328:NF-kappa B; C039060:artenimol