germacrone and Breast-Neoplasms

Germacrone, curdione, and furanodiene have been shown to be useful in the treatment of breast cancer but the pharmacological mechanism of action is unclear. In this paper, we explored a new method to study the molecular network and function of Traditional Chinese Medicine (TCM) herbs and their corresponding ingredients with bioinformatics tools, including PubChem Compound Database, BATMAN-TCM, SystemsDock, Coremine Medical, Gene ontology, and KEGG. Eleven targeted genes/proteins, 4 key pathways, and 10 biological processes were identified to participate in the mechanism of action in treating breast cancer with germacrone, curdione, and furanodiene. The information achieved by the bioinformatics tools was useful to interpretation the molecular mechanism for the treatment of germacrone, curdione, and furanodiene on breast cancers.

Topics: Breast Neoplasms; Computational Biology; Drugs, Chinese Herbal; Female; Furans; Heterocyclic Compounds, 2-Ring; Humans; MCF-7 Cells; Medicine, Chinese Traditional; Molecular Targeted Therapy; Sesquiterpenes, Germacrane

Estrogen receptor (ER)α-positive breast cancer cells regulate the expression of estrogen-responsive genes, which are involved in cell proliferation, differentiation, and cell cycle progression. Clinically, the inhibition of ERα-mediated gene expression in breast cancer cells has long been considered an effective way to prevent the development and progression of cancer. Germacrone, a terpenoid compound isolated from Rhizoma curcuma, has been known to have antitumor activity in various human cancer cell lines. However, the mechanism by which germacrone inhibits the proliferation of breast cancer cells is still unclear. Here, we demonstrated that germacrone inhibits ERα-mediated gene expression at the transcriptional level in MCF-7 cells. Germacrone inhibits the recruitment of ERα to the estrogen response element on chromatin and consequently compromises the binding of switch/sucrose non-fermentable chromatin remodeling complex and RNA polymerase II to target gene promoter, thereby inhibiting the estrogen-induced chromatin accessibility. In addition, germacrone efficiently potentiates the antitumor activity of methotrexate and 5-fluorouracil. Our results not only provide substantial molecular mechanism of germacrone on ERα-mediated signaling in breast cancer cells but also demonstrate the benefits of germacrone as a combination therapy with other drugs for the treatment of breast cancer. Copyright © 2016 John Wiley & Sons, Ltd.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Drugs, Chinese Herbal; Estrogen Receptor alpha; Female; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Sesquiterpenes, Germacrane; Signal Transduction

Traditional medicinal herbs are an untapped source of potential pharmaceutical compounds. This study aims to determine whether the proliferation of breast cancer cell lines could be inhibited by germacrone, a natural product isolated from Rhizoma curcuma. Germacrone treatment significantly inhibited cell proliferation, increased lactate dehydrogenase (LDH) release, and induced mitochondrial membrane potential (ΔΨm) depolarization in both MCF-7 and MDA-MB-231 cells in a dose-dependent manner. Germacrone induced MDA-MB-231 and MCF-7 cell cycle arrest at the G0/G1 and G2/M phases respectively and induced MDA-MB-231 cell apoptosis. Furthermore, germacrone treatment significantly increased Bok expression and cytochrome c release from mitochondria without affecting Bcl-2, Bcl-xL, Bax, and Bim protein expressions. In addition, germacrone treatment induced caspase-3, 7, 9, PARP cleavage. We concluded that germacrone inhibited the proliferation of breast cancer cell lines by inducing cell cycle arrest and apoptosis through mitochondria-mediated caspase pathway. These results might provide some molecular basis for the anti-tumor activity of Rhizoma curcuma.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Caspases; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cytochromes c; Drugs, Chinese Herbal; Female; Humans; L-Lactate Dehydrogenase; Membrane Potential, Mitochondrial; Sesquiterpenes, Germacrane; Signal Transduction