Natural Product Ginsenoside 25-OCH3-PPD Inhibits Breast Cancer Growth and Metastasis through Down-Regulating MDM2

Abstract

Although ginseng and related herbs have a long history of utility for various health benefits, their application in cancer therapy and underlying mechanisms of action are not fully understood. Our recent work has shown that 20(S)-25-methoxyl-dammarane-3β, 12β, 20-triol (25-OCH3-PPD), a newly identified ginsenoside from Panax notoginseng, exerts activities against a variety of cancer cells in vitro and in vivo. This study was designed to investigate its anti-breast cancer activity and the underlying mechanisms of action. We observed that 25-OCH3-PPD decreased the survival of breast cancer cells by induction of apoptosis and G1 phase arrest and inhibited the growth of breast cancer xenografts in vivo. We further demonstrated that, in a dose- and time-dependent manner, 25-OCH3-PPD inhibited MDM2 expression at both transcriptional and post-translational levels in human breast cancer cells with various p53 statuses (wild type and mutant). Moreover, 25-OCH3-PPD inhibited in vitro cell migration, reduced the expression of epithelial-to-mesenchymal transition (EMT) markers, and prevented in vivo metastasis of breast cancer. In summary, 25-OCH3-PPD is a potential therapeutic and anti-metastatic agent for human breast cancer through down-regulating MDM2. Further preclinical and clinical development of this agent is warranted.

The pyrido[b]indole MDM2 inhibitor SP-141 exerts potent therapeutic effects in breast cancer models

“…The effects of the test compound on human breast cancer cell growth and viability, expressed as the percentage of cell survival, were determined using the MTT assay as described previously [54][55][56] . Cells were grown in 96-well plates at 3-4 Â 10 3 cells per well, and were exposed to the test compound (0-25 mM) for 72 h. After incubation with the compound, 10 ml of the MTT solution (5 mg ml À 1 ; Sigma-Aldrich Co.) were added to each well.…”

“…The effects of SP-141 on cell proliferation were determined using the BrdUrd incorporation assay (Oncogene, La Jolla, CA, USA) as reported previously [54][55][56] . In brief, cells were seeded in 96-well plates (3-5 Â 10 3 cells per well) and incubated with various concentrations of SP-141 (0, 0.1, 0.2, 0.5 and 1 mM) for 24 h. BrdUrd was added to the medium 10 h before termination of the experiment.…”

“…Cells in early and late stages of apoptosis were detected using an Annexin V-FITC apoptosis detection kit from BioVision (Mountain View, CA, USA) according to the manufacturer's protocol, as described previously [54][55][56] . In this procedure, 2-3 Â 10 5 cells were exposed to the test compound (0, 0.2, 0.5 and 1 mM) and incubated for 48 h before the analysis.…”

“…To determine the effects of the compound on the cell cycle distribution using the method described previously [54][55][56] , cells (2-3 Â 10 5 per well) were exposed to the test compound (0, 0.2 or 0.5 mM) and incubated for 24 h before the analysis. The cells were then trypsinized, washed with PBS and fixed in 1.5 ml of 95% ethanol at 4°C overnight, followed by incubation with RNAse and staining with propidium iodide (Sigma-Aldrich Co.).…”

Phenotypic and Genetic Uniformity in Three Populations of <i>Panax notoginseng</i> by Mass Selection

“…Saponins in P. notoginseng roots are reported to have anti-inflammatory, cerebral-protective, hemostatic, and anti-tumor effects (Li and Chu, 1999;Jiang and Qian, 1995;White et al, 2000;Yin et al, 2012;Wang et al, 2012). Although the herb has long been widely cultivated commercially in the Wenshan region, a certified variety is unfortunately still not available.…”