Dihydroartemisinin inactivates NF-kappaB and potentiates the anti-tumor effect of gemcitabine on pancreatic cancer both in vitro and in vivo.
Gemcitabine is currently the best known chemotherapeutic option available for pancreatic cancer, but the tumor returns de novo with acquired resistance over time, which becomes a major issue for all gemcitabine-related chemotherapies. In this study, for the first time, we demonstrated that dihydroartemisinin (DHA) enhances gemcitabine-induced growth inhibition and apoptosis in both BxPC-3 and PANC-1 cell lines in vitro. The mechanism is at least partially due to DHA deactivates gemcitabine-induced NF-kappaB activation, so as to decrease tremendously the expression of its target gene products, such as c-myc, cyclin D1, Bcl-2, Bcl-xL. In our in vivo studies, gemcibabine also manifested remarkably enhanced anti-tumor effect when combined with DHA, as manifested by significantly increased apoptosis, as well as decreased Ki-67 index, NF-kappaB activity and its related gene products, and predictably, significantly reduced tumor volume. We concluded that inhibition of gemcitabine-induced NF-kappaB activation is one of the mechanisms that DHA dramatically promotes its anti-tumor effect on pancreatic cancer.
Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, PR China.
Shuang-Jia
SJ
Wang
Yue
Y
Gao
Hua
H
Chen
Rui
R
Kong
Hong-Chi
HC
Jiang
Shang-Ha
SH
Pan
Dong-Bo
DB
Xue
Xue-Wei
XW
Bai
Bei
B
Sun
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D037621:Artemisinins / Q000008:administration & dosage / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000378:metabolism; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D037621:Artemisinins; D004273:DNA, Neoplasm; D016328:NF-kappa B; D003841:Deoxycytidine; C039060:artenimol; D000093542:Gemcitabine