Ursolic acid inhibits growth and induces apoptosis in gemcitabine-resistant             human pancreatic cancer via the JNK and PI3K/Akt/NF-κB pathways.
Pancreatic cancer is one of the most deadly carcinomas worldwide. Although             gemcitabine as the standard chemotherapy agent has been proven to be effective,             the response rate remains at 5.4% and the 5-year survival rate is extremely poor.             Ursolic acid (UA) is a small molecule compound extracted from Chinese herbs as             well as edible vegetables and a well-known anti-inflammatory and immunosuppressive             agent. Here, we show that UA has potential to be developed into an anti-neoplastic             agent against gemcitabine-resistant pancreatic cancer and to explore its molecular             mechanism of action. In vitro, we used three different malignancy grades of pancreatic             resistant cancer cell lines including MIA PaCa-2, PANC-1 and Capan-1 to assess             the antitumor effect of UA. We found that UA inhibited growth and induced apoptosis             in a dose-dependent manner in all of the three pancreatic cancer cell lines. Both             extrinsic and intrinsic pathways were found to be involved in apoptotic cascade.             The potential signaling pathways are concerned with inactivation of the PI3K/Akt/NF-κB             pathway and activation of the c-Jun-terminal kinase (JNK) pathway. The JNK inhibitor             SP600125 partly abrogated the caspase-9 activation caused by UA. The Akt inhibitor             LY294002 did not mimic the effect of UA on caspase-8 and -9, but inhibited the             viability of MIA PaCa-2 cells to some extent. Equally, UA also overcame the chemoresistance             in the chemoresistant endometrial and ovarian carcinoma cell lines (HEC-1A and             OVCAR-3). Moreover, UA caused cytotoxicity to a nude mouse xenograft model in             vivo. Therefore, our present data suggest that UA can act as a novel and potent             therapeutic agent in gemcitabine-resistant pancreatic cancer and even as a promising             candidate in other chemoresistant cancers.
Center of Reproductive Medicine, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, PR China.
Jingjie
J
Li
Xiaoyan
X
Liang
Xing
X
Yang
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects; D014315:Triterpenes / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine; D000097245:Ursolic Acid
D000972:Antineoplastic Agents, Phytogenic; D003841:Deoxycytidine; D048031:JNK Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D014315:Triterpenes; D000093542:Gemcitabine; D000097245:Ursolic Acid