ginsenoside-rd and Breast-Neoplasms

Blockade of angiogenesis is an important approach for cancer treatment and prevention. In the present study, we investigated the effect of ginsenoside Rd (Rd) on angiogenesis in vitro and in vivo. Our results demonstrated that Rd inhibited vascular endothelial growth factor (VEGF)-induced migration, tube formation and proliferation of primary cultured human umbilical vascular endothelial cells (HUVECs) dose‑dependently. Furthermore, Rd abrogated VEGF-induced sprouting of the vessels from aortic rings, and inhibited vascular formation in the Matrigel plug assay in vivo. Under normoxic or hypoxic conditions, Rd suppressed VEGF‑induced activation of Akt/mammalian target of rapamycin (mTOR) signaling transduction cascades in HUVECs. When intraperitoneally administered to mice bearing human breast cancer (MDA‑MB-231) cell xenografts, Rd significantly decreased the volume and the weight of solid tumors in a dose-dependent manner, and decreased tumor angiogenesis as less Ki67- and CD31-positive cells were found. Additionally, we found that Rd inhibited proliferation and induced apoptosis as well as the inhibition of Akt/mTOR/P70S6 kinase signaling in breast cancer cells. Collectively, our findings revealed that Rd may be a promising anti-angiogenic drug with significant antitumor activity in human breast cancer.

Topics: Angiogenesis Inhibitors; Animals; Apoptosis; Breast Neoplasms; Cell Movement; Cell Proliferation; Female; Ginsenosides; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Pathologic; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; TOR Serine-Threonine Kinases; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Metastasis remains a major cause of mortality and poor prognosis in breast cancer patients. Anti-metastatic therapies are in great need to achieve optimal clinical outcome in breast cancer patients. Panax Notoginseng Saponins (PNS) has previously been shown to inhibit breast cancer metastasis in mouse. Here the potential anti-metastatic effect of one of the chemical compounds of PNS, ginsenoside Rd (Rd), was further evaluated in mouse mammary carcinoma 4T1 cells. The results revealed that Rd treatment dose-dependently suppressed cell migration and invasion in cultured 4T1 cells. In 4T1 cell-inoculated mice, Rd treatment led to decreased number of tumor lesions in lungs in both spontaneous and experimental metastasis models. Rd treatment resulted in increased expression of Smad2 in cultured 4T1 cells and in tumors grown from inoculated 4T1 cells. Rd treatment decreased the expression of microRNA (miR)-18a in cultured 4T1 cells and in tumors derived from inoculated 4T1 cells. Smad2 was further verified to be a direct target of miR-18a in 4T1 cells. The significant impact of Rd on counteracting miR-18a-medidated downregulation of Smad2 expression was also demonstrated. Together, the current work shows for the first time that Rd treatment attenuates breast cancer metastasis in part through derepressing miR-18a-mediated Smad2 expression regulation.

Topics: 3' Untranslated Regions; Animals; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Gene Expression Regulation, Neoplastic; Ginsenosides; Humans; Mice; MicroRNAs; Neoplasm Metastasis; RNA Interference; Smad2 Protein; Xenograft Model Antitumor Assays

MCF-7/ADR cells, a doxorubicin-resistant human breast cancer cell line, acquires resistance to several chemotherapeutic agents, such as anthracylines and taxol, via overexpression of the multidrug resistance1 (MDR1) gene. The present study was designed to clarify whether ginsenosides affect the expression of the MDR1 gene in MCF-7/ADR cells. Ginsenoside Rd, Re, Rb1, and Rg1 (100 microg/ml) decreased MDR1 protein levels in MCF-7/ADR cells. In particular, ginsenoside Rd most potently inhibited MDR1 protein expression without cytotoxicity, but did not change mRNA levels or nuclear levels of key transcriptional factors for MDR1 gene expression, hypoxia inducible factor-1alpha, CCAAT-enhancer binding protein beta, Forkhead box-containing protein, O subfamily1, or Y-box binding protein-1. Reporter gene analyses showed that ginsenoside Rd did not decrease MDR1 gene transcription or the pregnane X receptor reporter. MDR1 protein stability is dependent on ubiquitin-dependent protein degradation. We further found that ginsenosides Rd increased ubiquitination of MDR1. Moreover, doxorubicin resistance in MCF-7/ADR cells was reversed by ginsenoside Rd treatment. These results propose that ginseng administration with other anti-cancer agents may be useful for the treatment of chemotherapy-resistant breast cancer through down-regulating MDR1 protein.

Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Breast Neoplasms; Cell Line, Tumor; Doxorubicin; Drug Resistance; Gene Expression; Ginsenosides; Humans; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Ubiquitination