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12-O-Tetradecanoyl phorbol-13-acetate (TPA)-induced growth arrest is increased by silibinin by the down-regulation of cyclin B1 and cdc2 and the up-regulation of p21 expression in MDA-MB231 human breast cancer cells.

Abstract
TPA is a potent regulator of cell growth, including cell proliferation and differentiation. In this study, we determined the effect of silibinin on TPA-induced growth arrest in breast cancer cells. Silibinin increased growth arrest of the G2/M phase in a dose-dependent fashion. Silibinin decreased the basal level of cyclin B1 and cdc2 expression, which is involved in S phase and G2/M transition. In addition, TPA-induced G2/M phase arrest was increased by silibinin. Under the same conditions, TPA-induced down-regulation of cyclin B1 and cdc2 was decreased by silibinin. In contrast, TPA-induced p21 expression was further increased by silibinin. To determine the regulatory mechanism of TPA-induced growth arrest, we pretreated cells with various inhibitors, such as UO126, SB203580, and LY294002. Interestingly, TPA-induced growth arrest was significantly increased by LY294002, but not by UO126 and SB203580. In addition, TPA-induced down-regulation of cyclin B1 was inhibited by LY294002; however, the basal level of p21 was increased by TPA and TPA-induced p21 expression was further increased by LY294002. Finally, adenoviral constitutively active-Akt (Ad-CA-Akt) overexpression regulated the up-regulation of cyclin B1 and the down-regulation of p21. Therefore, we have demonstrated that silibinin has an additive effect on TPA-induced growth arrest through the PI-3-kinase/Akt-dependent pathway.
AuthorsSangmin Kim, Hye Sook Lee, Se-Kyung Lee, Sung Hoon Kim, Sung Mo Hur, Jee Soo Kim, Jung-Han Kim, Jun-Ho Choe, Incheol Shin, Jung-Hyun Yang, Jeong Eon Lee, Seok Jin Nam
JournalPhytomedicine : international journal of phytotherapy and phytopharmacology (Phytomedicine) Vol. 17 Issue 14 Pg. 1127-32 (Dec 01 2010) ISSN: 1618-095X [Electronic] Germany
PMID20554189 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2010 Elsevier GmbH. All rights reserved.
Chemical References
  • Antineoplastic Agents, Phytogenic
  • Cell Cycle Proteins
  • Cyclin B1
  • Cyclin-Dependent Kinase Inhibitor p21
  • Enzyme Inhibitors
  • Plant Extracts
  • Silymarin
  • Croton Oil
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • CDC2 Protein Kinase
  • Cdk1 protein, rat
  • Cyclin-Dependent Kinases
  • Tetradecanoylphorbol Acetate
Topics
  • Antineoplastic Agents, Phytogenic (pharmacology, therapeutic use)
  • Breast Neoplasms (drug therapy, metabolism)
  • CDC2 Protein Kinase
  • Cell Cycle (drug effects)
  • Cell Cycle Proteins (metabolism)
  • Cell Line, Tumor
  • Croton Oil (chemistry)
  • Cyclin B1 (metabolism)
  • Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
  • Cyclin-Dependent Kinases
  • Drug Synergism
  • Drug Therapy, Combination
  • Enzyme Inhibitors (pharmacology)
  • Female
  • Gene Expression Regulation, Neoplastic (drug effects)
  • Humans
  • Silybum marianum (chemistry)
  • Phosphatidylinositol 3-Kinases (metabolism)
  • Phytotherapy
  • Plant Extracts (pharmacology, therapeutic use)
  • Proto-Oncogene Proteins c-akt (metabolism)
  • Signal Transduction (drug effects)
  • Silymarin (pharmacology, therapeutic use)
  • Tetradecanoylphorbol Acetate (pharmacology, therapeutic use)

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