Ursolic acid causes apoptosis (cell death) in MCF-7 breast cancer cells, accompanied by a significant decrease in CyclinD1/CDK4 expression, which can be regulated by FoxM1. FoxM1 orchestrates the transcription of genes that are essential for cell cycle progression and cell proliferation. Ursolic acid inhibits FoxM1.
Mice whose ovaries had been removed were placed on a control diet or a diet containing (wt/wt) 0.05%, 0.10%, or 0.25% (≈54, 106, or 266 mg/kg body weight/day, respectively) ursolic acid. After 3 wks, mammary tumor cells were injected in the mammary fat pad, and mice continued on their respective diets for 5 more wk. All ursolic acid doses decreased tumor cell proliferation, as assessed by Ki67 immunostaining. Ursolic acid at 0.10% was most effective in inhibiting tumor growth and decreasing final tumor size. Modulation of Akt/mTOR signaling and induction of apoptosis appeared to mediate these effects on tumor growth. The equivalent dose for a 70 KG woman would be approximately 750 mg daily. Ursolic acid is present in high amounts in Greek sage (Salvia triloba) at 74,500 ppm, and in rosemary at 41,000 ppm.
Ursolic acid decreases the invasiveness and migration of breast cancer cells, deterrring metastases. This effect is linked with reduced activity of metalloproteinase-2 (MMP-2) and u-PA, and increased expression of tissue inhibitor of MMP-2 and plasminogen activator inhibitor-1, respectively. Ursolic acid suppressed the phosphorylation of Jun N-terminal kinase, Akt and mammalian target of rapamycin, but had no effect on the phosphorylation of ERK and p38. Ursolic acid also strongly reduced the levels of NFkappaB p65, c-Jun and c-Fos proteins in the nucleus of MDAMB231 cells. A time-dependent inhibition of the protein levels of Rho-like GTPases, growth factor receptor-bound protein 2, Ras and vascular endothelial growth factor in cytosol by ursolic acid treatment was also observed.
- Ursolic acid induces apoptosis by suppressing the expression of FoxM1 in MCF-7 human breast cancer cells.