Taiwanin A inhibits MCF-7 cancer cell activity through induction of oxidative stress, upregulation of DNA damage checkpoint kinases, and activation of p53 and FasL/Fas signaling pathways.

Abstract

This study investigates the anti-MCF-7 breast cancer cell effects and the underlying pharmacological activity and mechanism of taiwanin A, a major lignan isolated from Taiwania cryptomerioides. Our results show that taiwanin A time-dependently induced reactive oxygen species level and DNA damage in MCF-7 cells, which were likely activated kinases ataxia telangiectasia mutated (ATM) and checkpoint kinase (Chk). Taiwanin A could also up-regulate p53, phosphorylated p53, p21(Cip1), and p27(Kip1) and down-regulate the G(2)/M checkpoint cyclin-dependent kinase1 (Cdk1)-cyclin A/B, leading to induction of G(2)/M cell-cycle arrest in MCF-7 cells. Blockade of p53 gene expression by siRNA further demonstrated that the cell-cycle arrest induced by taiwanin A was p53-dependent. The FasL/Fas-mediated apoptotic signaling cascade was involved in taiwanin A-induced apoptosis via activation of caspases-10 and -7 (but not caspase-8), and proteolytic cleavage of poly(ADP-ribose) polymerase (PARP). In contrast, mitochondria-initiated apoptotic pathway was not involved. This is the first report to delineate novel mechanism of the action of taiwanin A against MCF-7 cells, suggesting this lignan may have value for development as an anti-breast cancer agent.

• Authors: Lie-Fen Shyur, Shu-Hua Lee, Shang-Tzen Chang, Chiu-Ping Lo, Yueh-Hsiung Kuo, Sheng-Yang Wang
• Journal: Phytomedicine : international journal of phytotherapy and phytopharmacology (Phytomedicine) Vol. 18 Issue 1 Pg. 16-24 (Dec 15 2010) ISSN: 1618-095X [Electronic] Germany
• PMID: 20637573 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier GmbH. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• FAS protein, human
• Furans
• Lignans
• Plant Extracts
• RNA, Small Interfering
• Reactive Oxygen Species
• Tumor Suppressor Protein p53
• fas Receptor
• taiwanin A
• Poly(ADP-ribose) Polymerases
• Polynucleotide 5'-Hydroxyl-Kinase
• Caspases

Topics

• Antineoplastic Agents, Phytogenic (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, metabolism)
• Caspases (metabolism)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cupressaceae (chemistry)
• DNA Damage (physiology)
• Female
• Furans (pharmacology, therapeutic use)
• Gene Expression (drug effects)
• Humans
• Lignans (pharmacology, therapeutic use)
• Oxidative Stress (drug effects)
• Phytotherapy
• Plant Extracts (pharmacology, therapeutic use)
• Plant Stems
• Poly(ADP-ribose) Polymerases (metabolism)
• Polynucleotide 5'-Hydroxyl-Kinase (metabolism)
• RNA, Small Interfering
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Up-Regulation
• fas Receptor (metabolism)