Development of chemoresistance, poor prognosis, and metastasis often renders the current treatments for colorectal cancer (CRC) ineffective. Whether ursolic acid (UA), a component of numerous medicinal plants, either alone or in combination with capecitabine, can inhibit the growth and metastasis of human CRC was investigated.
The effect of UA on proliferation of colorectal cancer cell lines was examined by mitochondrial dye-uptake assay, apoptosis by esterase staining, NF-κB activation by DNA binding assay and protein expression by western blot. The effect of UA on the growth and chemosensitization was also examined in orthotopically-implanted CRC in nude mice.
We found that UA inhibited the proliferation of different colon cancer cell lines. This is correlated with inhibition of constitutive NF-κB activation and downregulation of cell survival (Bcl-xL, Bcl-2, cFLIP, survivin), proliferative (Cyclin D1), and metastatic (MMP-9, VEGF, ICAM-1) proteins. When examined in an orthotopic nude-mice model, UA significantly inhibited tumor volume, ascites formation and distant organ metastasis, and this effect was enhanced with capecitabine. Immunohistochemistry of tumor tissue indicated that UA downregulated biomarkers of proliferation (Ki-67) and microvessel density (CD31). This effect was accompanied by suppression of NF-κB, STAT3, and β-catenin. In addition, UA suppressed EGFR, and induced p53, and p21 expression. We also observed bioavailability of UA in the serum and tissue of animals.
Overall our results demonstrate that UA can inhibit the growth and metastasis of CRC and further enhance the therapeutic effects of capecitabine through suppression of multiple biomarkers linked to inflammation, proliferation, invasion, angiogenesis, and metastasis.