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-kappa B 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.