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

• Published in: Phytomedicine (Stuttgart) Vol. 18; no. 1; pp. 16 - 24
• Main Authors: Shyur, Lie-Fen, Lee, Shu-Hua, Chang, Shang-Tzen, Lo, Chiu-Ping, Kuo, Yueh-Hsiung, Wang, Sheng-Yang
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 15.12.2010; Urban & Fischer Verlag
• Subjects: Antineoplastic Agents, Phytogenic - pharmacology; Antineoplastic Agents, Phytogenic - therapeutic use; Apoptosis - drug effects; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Cancer cells; Caspases - metabolism; Cell Cycle - drug effects; Cell Line, Tumor; Cupressaceae - chemistry; DNA damage; DNA Damage - physiology; DNA damage checkpoint kinases; fas Receptor - metabolism; FasL/Fas signaling pathway; Female; Furans - pharmacology; Furans - therapeutic use; Gene Expression - drug effects; Health aspects; Humans; Lignans - pharmacology; Lignans - therapeutic use; Medicine, Botanic; Medicine, Herbal; Oxidative stress; Oxidative Stress - drug effects; Physiological aspects; Phytotherapy; Plant Extracts - pharmacology; Plant Extracts - therapeutic use; Plant Stems; Poly(ADP-ribose) Polymerases - metabolism; Polynucleotide 5'-Hydroxyl-Kinase - metabolism; Reactive Oxygen Species - metabolism; RNA, Small Interfering; Signal Transduction - drug effects; Taiwania cryptomerioides; Taiwanin A; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Up-Regulation; Taiwan; Oxidative stress; PCNA; Taiwanin A; Chk; DAPI; PARP; Breast cancer; FasL/Fas signaling pathway; Cdk; MTT; CKIs; RB; NAC; Taiwania cryptomerioides; PI; ATM; DNA damage checkpoint kinases
• ISSN: 0944-7113; 1618-095X
• DOI: 10.1016/j.phymed.2010.06.005

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.