Ursolic acid inhibits the proliferation of various tumor cell lines


The in vitro anti-tumor activity of ursolic acid was reviewed in 2001. In addition to its anti-inflammatory activity, ursolic acid reduces the proliferation of many tumor cell lines and many possible mechanisms of action have been addressed. Studies in B16 cells and MCF-7 breast carcinoma cells showed an early G1 cytostatic effect for ursolic acid. Enhancement of intracellular Ca2+ signaling is thought to play a role in reducing proliferation.

Ursolic acid’s ability to induce apoptosis in many different cell types is likely to play a major role in its anti-proliferative activity. In HT-29 colon cells, ursolic acid decreased proliferation by induction of apoptosis accompanied by activation of caspases-3, 8 and 9. Ursolic acid-induced apoptosis in HL-60 leukemia cells was observed to be mediated by intracellular Ca2+ release.

In human prostate cells, apoptosis was accompanied by enhanced release of cytochrome c, caspase activation, and down-regulation of inhibitor of apoptosis proteins (c-IAPs). Increased expression of p21WAF1, a gene regulated by p53 and thought to induce tumor suppression through inhibition of cyclin-dependent kinases (CDKs), has also been reported.

In B16F-10 melanoma cells, ursolic acid at non-cytotoxic concentrations resulted in apoptosis accompanied by upregulation of the tumor suppressor gene p53 and caspase-3 and down-regulation of anti-apoptotic gene Bcl-2. This decrease in NF-KB-mediated activation of Bcl-2 occurred with the inhibition of several transcription factors in the NF-KB pathway.

A reduction was seen in the expression of pro-inflammatory cytokines IL-1B and IL-6, and TNF-alpha and GM-CSF. Caspase-3 activation by ursolic acid through the mitochondrial pathway with upregulation of pro-apototic Bax and a decrease in Bcl-2 was reported in M4Beu human melanoma cells.

Studies in an endometrial cancer cell line SNG-II showed that treatment with 50 micro M ursolic acid decreased activation of the phosphatidylinositol-3-kinase-Akt (PI3K-Akt) pathway and the mitogen activated protein kinase (MAPK) pathways, which are associated with the high level of Akt phosphorylation often seen in endometrial tumors.

Ursolic acid has been shown to decrease the expression of matrix metalloproteinase-9 (MMP-9). Matrix metalloproteinase activities are involved in the remodeling of the extracellular matrix, part of the tumor micro-environment, and are thus linked to tumor invasion and increased risk of metastasis. Ursolic acid has been shown to decrease cell viabililty and induce apoptosis in prostate cancer cells.

Since prostate cancers often metastasize, the effects of cranberry constituents on matrix metalloproteinase expression in DU-145 prostate tumor cells were studied. The hydroxycinnamoyl esters of ursolic acid were evaluated in a DU-145 prostate tumor model and were found to strongly inhibit expression of both MMP- 2 and MMP-9 at micromolar concentrations. While polyphenolics from cranberry fruit also inhibited MMP expression, the triterpenoids were observed to do so at much lower concentrations.

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