Oridonin enhances antitumor activity of gemcitabine in pancreatic cancer             through MAPK-p38 signaling pathway.
Gemcitabine is currently the best treatment available for pancreatic cancer (PaCa); however, patients with the disease develop resistance to the drug over time. Agents that can either enhance the effects of gemcitabine or overcome chemoresistance to the drug are required for the treatment of PaCa. Oridonin is one such agent which is safe and multitargeted, and has been linked with the suppression of survival, proliferation, invasion and angiogenesis of cancer. In this study, we investigated whether oridonin could sensitize PaCa to gemcitabine in vitro and in vivo. In vitro, oridonin inhibited the proliferation of the PaCa cell line, BxPC-3, potentiated the apoptosis induced by gemcitabine, induced G1 cell cycle arrest and activated p38 and p53; these results were significant when oridonin was combined with gemcitabine. In vivo, we found that oridonin significantly suppressed tumor growth and this effect was further enhanced by gemcitabine (P<0.05). Tumors from nude mice injected with BxPC-3 PaCa cells and treated with a combination of oridonin and gemcitabine showed a significant upregulation in p38 and p53 activation (P<0.05 vs. control, P<0.05 vs. gemcitabine or oridonin alone). Taken together, our results demonstrate that oridonin can potentiate the effects of gemcitabine in PaCa through the mitogen-activated protein kinase (MAPK)-p38 signaling pathway, which is dependent on p53 activation.
Department of Hepatobiliary-Pancreatic Surgery, The Second Affiliated                     Hospital of Wenzhou Medical College, Wenzhou, Zhejiang, P.R. China.
He-Qi
HQ
Bu
Jiang
J
Luo
Hui
H
Chen
Jian-Hong
JH
Zhang
Hong-Hai
HH
Li
Hong-Chun
HC
Guo
Zhao-Hong
ZH
Wang
Sheng-Zhang
SZ
Lin
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D045786:Diterpenes, Kaurane / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011897:Random Allocation; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000378:metabolism*; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D045786:Diterpenes, Kaurane; D016159:Tumor Suppressor Protein p53; C011959:oridonin; D003841:Deoxycytidine; D048051:p38 Mitogen-Activated Protein Kinases; D000093542:Gemcitabine