protopanaxadiol and Breast-Neoplasms

Ginsenosides are the major and key components for ginseng to exert its wide and beneficial therapeutic efficacy in clinic. Meanwhile, many ginsenosides and their metabolites showed in vitro an in vivo anti-tumor activity, among which ginsenoside Rb1 has attracted much attention due to its good solubility and amphipathy. In this study, the self-assembly behavior of Rb1 was investigated and the Rb1 nano-assembly could further stabilize or encapsulated hydrophobic drugs such as protopanaxadiol (PPD) and paclitaxel (PTX) to form nanoparticles, based on which, a natural nanoscale drug delivery system, ginsenoside Rb1 stabilized and PTX/PPD co-loaded nanoparticles (GPP NPs) were prepared. The resultant GPP NPs exhibited a small particle size of 126.2 nm, a narrow size distribution (PDI=0.145), and a zeta potential of -27.3 mV. PTX loading content was 11.06% with an encapsulation efficiency of 93.86%. GPP NPs were spherical and stable in normal saline, 5% glucose, PBS, plasma, or on-shelf storage for 7 days. Both PTX and PPD existed in an amorphous state in GPP NPs and were released in a sustained pattern. GPP NPs showed 10-fold higher in vitro anti-tumor activity of than PTX injections. In the in vivo experiment, GPP NPs achieved a much higher tumor inhibition rate than PTX injections (64.95% vs 43.17%, P < 0.01) and certain tumor target ability. In conclusion, GPP NPs had significantly enhanced anti-tumor efficacy and improved tumor microenvironment, thus were promising to be developed into a novel anti-tumor agent for the treatment of breast tumor.

Topics: Breast Neoplasms; Cell Line, Tumor; Female; Ginsenosides; Humans; Nanoparticles; Paclitaxel; Retinoblastoma Binding Proteins; Tumor Microenvironment; Ubiquitin-Protein Ligases

20(S)-Protopanaxadiol (PPD), a ginsenoside isolated from Pananx quinquefolium L., has been shown to inhibit growth and proliferation in several cancer cell lines. The aim of this study was to evaluate its anticancer activity in human breast cancer cells. MCF-7 cells were incubated with different concentrations of 20(S)-PPD and cytotoxicity was evaluated by MTT assay. Occurrence of apoptosis was detected by DAPI and Annexin V-FITC/PI double staining. Mitochondrial membrane potential was measured with Rhodamine 123. The Bcl-2 and Bax expression were determined by Western blot analysis. Caspase activity was measured by colorimetric assay. 20(S)-PPD dose-dependently inhibited cell proliferation in MCF-7 cells, with an IC50 value of 33.3 μM at 24h. MCF-7 cells treated with 20(S)-PPD presented typical apoptosis, as observed by morphological analysis in cell stained with DAPI. The percentages of annexin V-FITC positive cells were 8.92%, 17.8%, 24.5% and 30.5% in MCF-7 cells treated with 0, 15, 30 and 60μM of 20(S)-PPD, respectively. Moreover, 20(S)-PPD could induce mitochondrial membrane potential loss, up-regulate Bax expression and down-regulate Bcl-2 expression. These events paralleled activation of caspase-9, -3 and PARP cleavage. Apoptosis induced by 20(S)-PPD was blocked by z-VAD-fmk, a pan-caspase inhibitor, suggesting induction of caspase-mediated apoptotic cell death. In conclusion, the 20(S)-PPD investigated is able to inhibit cell proliferation and to induce cancer cell death by a caspase-mediated apoptosis pathway.

Topics: Antidepressive Agents; Apoptosis; Blotting, Western; Breast Neoplasms; Caspases; Cell Proliferation; Cytochromes c; Female; Humans; Membrane Potential, Mitochondrial; Mitochondria; Sapogenins; Signal Transduction; Tumor Cells, Cultured

Protopanaxadiol (PPD), an aglycon of ginseng saponins, has shown anticancer activity in earlier studies. Here, we have reported the semisynthesis of nine PPD derivatives with acetyl substitutions. Subsequently, the antiproliferative effects of these nine analogs on different human cancer cell lines have been investigated. Compounds 1, 3, and 5 showed more significant and more potent antiproliferative activity compared with PPD and other derivatives. A flow cytometric assay indicated that compounds 1, 3, and 5 arrested cell cycle progression in the G1 phase and significantly induced apoptosis of cancer cells.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Breast Neoplasms; Cell Growth Processes; Cell Line, Tumor; Colorectal Neoplasms; Drug Screening Assays, Antitumor; Female; G1 Phase; HCT116 Cells; Humans; Magnetic Resonance Spectroscopy; Panax; Sapogenins; Saponins; Structure-Activity Relationship

20S-protopanaxadiol (aPPD) is a major gastrointestinal metabolic product of ginsenosides. The latter share structural similarity with steroids and are the main pharmacologically active component in ginseng.. The authors investigated the interaction between aPPD and estrogen receptors (ER) in human breast adenocarcinoma MCF-7 cells through receptor binding assay, ER-induced gene expression, and cell proliferation both in vitro and in vivo.. aPPD, but not its close analog ginsenosides, competed with the [(3)H]-17-beta estradiol (E2) for ER with IC(50) at 26.3 microM. aPPD alone weakly induced luciferase reporter-gene expression controlled by an estrogen-regulated element, which was completely blocked by tamoxifen. aPPD alone, or in synergy with tamoxifen, blocked E2-induced transcriptional activation. aPPD also inhibited colony formation of endometrial cancer cells. aPPD potently inhibited estrogen-stimulated MCF-7 cell proliferation and synergistically enhanced the cytotoxicity of tamoxifen on both ER+ MCF-7 and ER- MDA-MB231 cells. Furthermore, aPPD, but not tamoxifen, inhibited Akt phosphorylation. Growth of MCF-7 xenograft tumor supplemented with E2 was completely inhibited in animals treated with aPPD, tamoxifen, or aPPD plus tamoxifen.. These results suggested that aPPD inhibits estrogen-stimulated gene expression and cell proliferation in ER-positive breast cancer cells. In addition, aPPD synergistically enhances cytotoxicity of tamoxifen in an ER-independent fashion, probably by down-regulating Akt activity.

Topics: Adenocarcinoma; Animals; Blotting, Western; Breast Neoplasms; Cell Proliferation; Drug Synergism; Estrogen Antagonists; Female; Humans; Mice; Mice, SCID; Panax; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptors, Estrogen; Sapogenins; Tamoxifen; Transplantation, Heterologous; Triterpenes; Tumor Cells, Cultured