Targeting beta-catenin signaling to induce apoptosis in human breast cancer cells by z-guggulsterone and Gugulipid extract of Ayurvedic medicine plant Commiphora mukul.

Abstract

BACKGROUND:

z-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.

METHODS:

Using 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.

RESULTS:

GL 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.

CONCLUSION:

The present study indicates that the β-Catenin signaling pathway is the target for GL-induced growth inhibition and apoptosis in human breast cancer.

• Authors: Guoqin Jiang, Xiao Xiao, Yan Zeng, Kalyanam Nagabhushanam, Muhammed Majeed, Dong Xiao
• Journal: BMC complementary and alternative medicine (BMC Complement Altern Med) Vol. 13 Pg. 203 (Aug 03 2013) ISSN: 1472-6882 [Electronic] England
• PMID: 23914993 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
• Plant Extracts
• Plant Gums
• Pregnenediones
• TCF4 protein, human
• Transcription Factor 4
• Transcription Factors
• beta Catenin
• guggulu extract
• pregna-4,17-diene-3,16-dione

Topics

• Apoptosis (drug effects)
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors (genetics, metabolism)
• Breast Neoplasms (genetics, metabolism, physiopathology)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Commiphora (chemistry)
• Humans
• Medicine, Ayurvedic
• Plant Extracts (pharmacology)
• Plant Gums (pharmacology)
• Pregnenediones (pharmacology)
• Protein Binding
• Signal Transduction (drug effects)
• Transcription Factor 4
• Transcription Factors (genetics, metabolism)
• beta Catenin (metabolism)