Novel quinolone CHM-1 induces apoptosis and inhibits metastasis in a human osterogenic sarcoma cell line.

Abstract

Novel 2-phenyl-4-quinolone compounds have potent cytotoxic effects on different human cancer cell lines. In this study, we examined anticancer activity and mechanisms of 20-fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone (CHM-1) in human osterogenic sarcoma U-2 OS cells. CHM-1-induced apoptosis was determined by flow cytometric analysis, DAPI staining, Comet assay, and caspase inhibitors. CHM-1-inhibited cell migration and invasion was assessed by a wound healing assay, gelatin zymography, and a Transwell assay. The mechanisms of CHM-1 effects on apoptosis and metastasis signaling pathways were studied using Western blotting and gene expression. CHM-1 induced G2/M arrest and apoptosis at an IC(50) (3 microM) in U-2 OS cells and caspase-3, -8, and -9 were activated. Caspase inhibitors increased cell viability after exposure to CHM-1. CHM-1-induced apoptosis was associated with enhanced ROS generation, DNA damage, decreased DeltaPsi(m) levels, and promotion of mitochondrial cytochrome c release. CHM-1 stimulated mRNA expression of caspase-3, -8, and -9, AIF, and Endo G. In addition, CHM-1 inhibited cell metastasis at a low concentration (<3 microM). CHM-1 inhibited the cell metastasis through the inhibition of MMP-2, -7, and -9. CHM-1 also decreased the levels of MAPK signaling pathways before leading to the inhibition of MMPs. In summary, CHM-1 is a potent inducer of apoptosis, which plays a role in the anticancer activity of CHM-1.

• Authors: Shu-Chun Hsu, Jai-Sing Yang, Chao-Lin Kuo, Chyi Lo, Jing-Pin Lin, Te-Chun Hsia, Jen-Jyh Lin, Kuang-Chi Lai, Hsiu-Maan Kuo, Li-Jiau Huang, Sheng-Chu Kuo, W Gibson Wood, Jing-Gung Chung
• Journal: Journal of orthopaedic research : official publication of the Orthopaedic Research Society (J Orthop Res) Vol. 27 Issue 12 Pg. 1637-44 (Dec 2009) ISSN: 1554-527X [Electronic] United States
• PMID: 19557855 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2'-fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone
• Antineoplastic Agents
• Caspase Inhibitors
• Dioxoles
• Enzyme Inhibitors
• Matrix Metalloproteinase Inhibitors
• Quinolones
• Reactive Oxygen Species
• Mitogen-Activated Protein Kinases
• Caspases

Topics

• Antineoplastic Agents (pharmacology)
• Bone Neoplasms (drug therapy, genetics, pathology)
• Caspase Inhibitors
• Caspases (biosynthesis)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Survival (drug effects)
• Comet Assay
• DNA Damage
• Dioxoles (pharmacology)
• Drug Screening Assays, Antitumor
• Enzyme Inhibitors (pharmacology)
• Gene Expression (drug effects)
• Humans
• MAP Kinase Signaling System (drug effects)
• Matrix Metalloproteinase Inhibitors
• Mitogen-Activated Protein Kinases (metabolism)
• Osteosarcoma (drug therapy, genetics, pathology)
• Quinolones (pharmacology)
• Reactive Oxygen Species (metabolism)