Abstract
Backgroundz-Guggulsterone (z-Gug) and Gugulipid (GL) have been used to treat a variety of ailments. We now report their anti-cancer effect and mechanism against human breast cancer.MethodsUsing the human estrogen receptor-positive (MCF-7) and triple-negative (MDA-MB-231) breast cancer cells as well as the normal human mammary epithelial cell line (HMEC), we evaluated the anti-breast-cancer efficacy and apoptosis inducing activity of GL. We determined the cellular and molecular mechanism of GL-inhibited breast cancer cell growth.ResultsGL significantly inhibited growth of MCF-7 and MDA-MB-231 cells with an IC50~2 μM at pharmacologically relevant concentrations standardized to its major active constituent z-Gug. The GL-induced growth inhibition correlated with apoptosis induction as evidenced by an increase in cytoplasmic histone-associated DNA fragmentation and caspase 3 activity. The GL-induced apoptosis was associated with down-regulation of the β-Catenin signaling pathway. The decreased expression of Wnt/β-Catenin targeting genes, such as cyclin D1, C-myc and survivin, and the inhibition of the activity of the transcription factor (T-cell factor 4, TCF-4) were observed in GL-treated breast cancer cells. The GL treatment resulted in a significant reduction of β-Catenin /TCF-4 complex in both of the cancer cells. The GL-induced apoptotic cell death was significantly enhanced by RNA Interference of β-Catenin and TCF-4. On the other hand, the normal human mammary epithelial cell HMEC, compared with the human breast cancer cells, is significantly more resistant to growth inhibition and apoptosis induction by GL.ConclusionThe present study indicates that the β-Catenin signaling pathway is the target for GL-induced growth inhibition and apoptosis in human breast cancer.
Highlights
Despite significant advances toward targeted therapy and screening techniques, breast cancer continues to be the leading cause of cancer-related deaths and the most frequently diagnosed cancer among women in the USAGugulipid (GL, guggul, guggal, or gugul lipid) is the ethyl acetate extract of the gum guggul resin harvested directly from the Commiphora mukul tree
The results have shown that z-Gug significantly inhibits the proliferation of PC-3, LNCaP and DU145 human prostate cancer cells, but not that of the normal human prostate epithelial cell line PrEC [14,15,16]
GL inhibited human breast cancer cell growth but not normal human mammary epithelial cell line HMEC Initially, the colonogenic assay was used to determine the effect of GL on cell viability
Summary
Despite significant advances toward targeted therapy and screening techniques, breast cancer continues to be the leading cause of cancer-related deaths and the most frequently diagnosed cancer among women in the USAGugulipid (GL, guggul, guggal, or gugul lipid) is the ethyl acetate extract of the gum guggul resin (raw material) harvested directly from the Commiphora mukul tree (family name: Burseraceae; synonyms: Hook, Bandari, Balsamodendron mukul, and Commiphora Wightii). The results have shown that z-Gug significantly inhibits the proliferation of PC-3, LNCaP and DU145 human prostate cancer cells, but not that of the normal human prostate epithelial cell line PrEC [14,15,16] Based on these data, we hypothesized that GL might be more effective in the growth inhibition of prostate cancer cells because it contains a number of steroids, including the two isomers z- and E-Gugs. Our data were the first to show that GL has a stronger anti-cancer potential in human prostate cancer cells than z-Gug, one of its active constituents, as evidenced by greater inhibition of cell growth [13]. We were the first to report the anti-cancer effect and mechanism of GL on human breast cancer cells
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