Abstract
Platycodin D (PD), a major saponin derived from Platycodin grandiflorum, exerted cytotoxicity against prostate cancer cell lines (PC3, DU145 and LNCaP cells) with IC₅₀ values in the range of 11.17 to 26.13 μmol/L, whereas RWPE-1 cells (a non-malignant human prostate epithelial cell line) were not significantly affected. A further study in these cell lines showed that PD could potently affect cell proliferation (indicated by the bromodeoxyuridine assay), induce cell apoptosis (determined by Annexin V-FITC flow cytometry) and cause cell cycle arrest (indicated by PI staining). After being treated with PD for 48 hours, DU145 and LNCaP cells were arrested in the G0 /G1 phase, and PC3 cells were arrested in the G2/M phase. A Western blotting analysis indicated that PD increased the expression of the FOXO3a transcription factor, decreased the expression of p-FOXO3a and MDM2 and increased the expression of FOXO-responsive genes, p21 and p27. MDM2 silencing (transiently by siRNA-MDM2) increased the PD-induced FOXO3a protein expression, while MDM2 overexpression (in cells transiently transfected with a pcDNA3-MDM2 plasmid) decreased the PD-induced expression of the FOXO3a protein. Moreover, PD dose-dependently inhibited the growth of PC3 xenograft tumors in BALB/c nude mice. A Western blotting analysis of the excised xenograft tumors indicated that similar changes in protein expression also occurred in vivo. These results suggest that PD exhibits significant activity against prostate cancer in vitro and in vivo. The FOXO3a transcription factor appears to be involved in the activity of PD. Together, all of these findings provide a basis for the future development of this agent for human prostate cancer therapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents, Phytogenic / administration & dosage
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Antineoplastic Agents, Phytogenic / adverse effects
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Antineoplastic Agents, Phytogenic / pharmacology
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Antineoplastic Agents, Phytogenic / therapeutic use*
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Apoptosis / drug effects*
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Cell Line
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Dose-Response Relationship, Drug
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Forkhead Box Protein O3
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Forkhead Transcription Factors / agonists*
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / metabolism
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Gene Expression Regulation, Neoplastic / drug effects*
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Gene Silencing
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Humans
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Male
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Mice, Nude
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Neoplasm Proteins / agonists
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Prostate / drug effects*
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Prostate / metabolism
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Prostate / pathology
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Prostatic Neoplasms / drug therapy*
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-mdm2 / genetics
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Proto-Oncogene Proteins c-mdm2 / metabolism
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Random Allocation
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Recombinant Proteins / chemistry
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Recombinant Proteins / metabolism
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Resting Phase, Cell Cycle / drug effects
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Saponins / administration & dosage
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Saponins / adverse effects
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Saponins / pharmacology
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Saponins / therapeutic use*
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Specific Pathogen-Free Organisms
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Triterpenes / administration & dosage
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Triterpenes / adverse effects
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Triterpenes / pharmacology
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Triterpenes / therapeutic use*
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Tumor Burden / drug effects
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents, Phytogenic
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FOXO3 protein, human
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Forkhead Box Protein O3
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Forkhead Transcription Factors
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Neoplasm Proteins
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Recombinant Proteins
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Saponins
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Triterpenes
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platycodin D
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2