7,8-dihydroxy-3-(4'-hydroxyphenyl)coumarin inhibits invasion and migration of osteosarcoma cells.. Mus musculus strain:C3H/HeJ

Advances in pharmacy and medicine have led to the development of many anti-cancer and molecular targeted agents; however, there are few agents capable of suppressing metastasis. To prevent cancer recurrence, it is essential to develop novel agents for inhibiting metastasis. Coumarin-based compounds have multiple pharmacological activities including anti-cancer effects. We screened a compound library constructed at Kyoto Pharmaceutical University and showed that 7,8-dihydroxy-3-(4'-hydroxyphenyl)coumarin (DHC) inhibited invasion and migration of LM8 and 143B osteosarcoma cells in a concentration-dependent manner. DHC inhibited the migration of LM8 cells in spheroid cultures. DHC decreased intercellular actin filament formation by downregulating small GTP-binding proteins such as RhoA, Rac1, and Cdc42, which regulate actin reorganization. However, DHC did not downregulate the corresponding mRNA transcripts, whereas it downregulated small GTP-binding proteins in the presence of cycloheximide, suggesting that DHC induces the degradation of these proteins. DHC treatment inhibited metastasis and prolonged overall survival in a spontaneous metastasis mouse model. These results indicate that DHC has the potential to suppress metastasis of osteosarcoma cells by downregulating small GTP-binding proteins.