The development of chemoresistance in human
pancreatic cancer is one reason for the poor survival rate for patients with this
cancer. Because multiple gene products are linked with chemoresistance, we investigated the ability of
ursolic acid (UA) to sensitize
pancreatic cancer cells to
gemcitabine, a standard drug used for the treatment of
pancreatic cancer. These investigations were done in AsPC-1, MIA PaCa-2, and Panc-28 cells and in nude mice orthotopically implanted with Panc-28 cells. In vitro, UA inhibited proliferation, induced apoptosis, suppressed NF-κB activation and its regulated proliferative, metastatic, and
angiogenic proteins. UA (20 μM) also enhanced
gemcitabine (200 nM)-induced apoptosis and suppressed the expression of NF-κB-regulated
proteins. In the nude mouse model,
oral administration of UA (250 mg/kg) suppressed
tumor growth and enhanced the effect of
gemcitabine (25 mg/kg). Furthermore, the combination of UA and
gemcitabine suppressed the
metastasis of
cancer cells to distant organs such as liver and spleen. Immunohistochemical analysis showed that
biomarkers of proliferation (Ki-67) and microvessel density (CD31) were suppressed by the combination of UA and
gemcitabine. UA inhibited the activation of NF-κB and STAT3 and the expression of tumorigenic
proteins regulated by these inflammatory
transcription factors in
tumor tissue. Furthermore, the combination of two agents decreased the expression of miR-29a, closely linked with
tumorigenesis, in the
tumor tissue. UA was found to be bioavailable in animal serum and
tumor tissue. These results suggest that UA can inhibit the growth of human pancreatic
tumors and sensitize them to
gemcitabine by suppressing inflammatory
biomarkers linked to proliferation, invasion, angiogenesis, and
metastasis.