DDTD, an isoflavone derivative, induces cell apoptosis through the reactive oxygen species/apoptosis signal-regulating kinase 1 pathway in human osteosarcoma cells.

Abstract

Osteosarcoma is the most common primary bone tumor associated with childhood and adolescence. In the present study, we investigated the anticancer effect of a new isoflavone derivative, 3',4'-dichloro-3-(3,4-dichlorophenylacetyl)-2,4,6-trihydroxydeoxybenzoin (DDTD) in human osteosarcoma cells. DDTD induced cell apoptosis in human osteosarcoma cell lines (including: U2OS, MG-63, Saos2 and ROS 17/2.8). We found that the accumulation of reactive oxygen species is a critical mediator in DDTD-induced cell death. DDTD induced apoptosis signal-regulating kinase 1 (ASK1) dephosphorylation and its dissociation from 14-3-3. Treatment of osteosarcoma cells with DDTD induced p38 and p53 phosphorylation. Transfection with ASK1, mitogen activated protein kinase (MAPK) kinase (MKK)3/6, and p38 small interfering RNA (siRNA) antagonized the DDTD-induced cell apoptosis. DDTD also triggered the mitochondrial apoptotic pathway, as indicated by a change in Bax/Bcl2 ratio and Caspase-9 activation. Bax knockdown using a Bax siRNA strategy reduced Bax expression and subsequent cell death. In addition, transfection of cells with ASK1, MKK3/6, and p38 siRNA reduced DDTD-induced p38 activation, p53 phosphorylation and Bax expression. These results suggest that DDTD generates reactive oxygen species and activates the ASK1-MKK3/6-p38-p53-Bax pathway to cause osteosarcoma cell death.

• Authors: Jung-Tsan Chen, Yi-Chin Fong, Te-Mao Li, Ju-Fang Liu, Che-Wei Hsu, Chih-Shiang Chang, Chih-Hsin Tang
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 597 Issue 1-3 Pg. 19-26 (Nov 12 2008) ISSN: 0014-2999 [Print] Netherlands
• PMID: 18822283 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 14-3-3 Proteins
• 3',4'-dichloro-3-(3,4-dichlorophenylacetyl)-2,4,6-trihydroxydeoxybenzoin
• Antineoplastic Agents, Phytogenic
• BAX protein, human
• Isoflavones
• Phytoestrogens
• Proto-Oncogene Proteins c-bcl-2
• RNA, Small Interfering
• Reactive Oxygen Species
• TP53 protein, human
• Tumor Suppressor Protein p53
• bcl-2-Associated X Protein
• p38 Mitogen-Activated Protein Kinases
• MAP Kinase Kinase Kinase 5
• MAP3K5 protein, human
• MAP Kinase Kinase 3
• MAP Kinase Kinase 6
• MAP2K3 protein, human
• MAP2K6 protein, human
• CASP9 protein, human
• Caspase 9

Topics

• 14-3-3 Proteins (metabolism)
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Caspase 9 (metabolism)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Humans
• Isoflavones (pharmacology)
• MAP Kinase Kinase 3 (metabolism)
• MAP Kinase Kinase 6 (metabolism)
• MAP Kinase Kinase Kinase 5 (genetics, metabolism)
• Mitochondria (enzymology, pathology)
• Osteosarcoma (enzymology, genetics, pathology)
• Phosphorylation
• Phytoestrogens (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• RNA Interference
• RNA, Small Interfering (metabolism)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• Time Factors
• Transfection
• Tumor Suppressor Protein p53 (metabolism)
• bcl-2-Associated X Protein (metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)