Novel quinolone CHM-1 induces apoptosis and inhibits metastasis in a human osterogenic sarcoma cell line.
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.
Hsu
Shu-Chun
SC
School of Nutrition, China Medical University, Taichung, Taiwan.
Yang
Jai-Sing
JS
Kuo
Chao-Lin
CL
Lo
Chyi
C
Lin
Jing-Pin
JP
Hsia
Te-Chun
TC
Lin
Jen-Jyh
JJ
Lai
Kuang-Chi
KC
Kuo
Hsiu-Maan
HM
Huang
Li-Jiau
LJ
Kuo
Sheng-Chu
SC
Wood
W Gibson
WG
Chung
Jing-Gung
JG
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D061945:Caspase Inhibitors; D020169:Caspases / Q000096:biosynthesis; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D020552:Comet Assay; D004249:DNA Damage; D004149:Dioxoles / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D061965:Matrix Metalloproteinase Inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D012516:Osteosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015363:Quinolones / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
C525063:2'-fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone; D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D004149:Dioxoles; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D015363:Quinolones; D017382:Reactive Oxygen Species; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases