Dual Genotoxic and Antigenotoxic Effects of 3-Benzoylcoumarins in Mammalian Cells.

Abstract

Coumarins are phenolic compounds widely recognized for their diverse pharmacological activities and have attracted increasing attention as potential chemopreventive agents. In the present study, four known 3-benzoylcoumarin derivatives [(1), (2), (3), and (4)] were evaluated for their cytotoxic, mutagenic, and antigenotoxic effects in Chinese hamster lung fibroblasts (V79 cells). Cytotoxicity was initially assessed using the MTT assay to establish sub-cytotoxic concentrations for subsequent analyses. Genotoxicity and chemopreventive activity were investigated using the cytokinesis-block micronucleus (CBMN) assay following DNA damage induced by doxorubicin (DXR) or methyl methanesulfonate (MMS). All compounds exhibited concentration-dependent cytotoxicity, with (2) showing the greatest potency. In the CBMN assay, none of the compounds significantly altered the nuclear division index (NDI), indicating the absence of cytostatic effects. However, at higher concentrations, the derivatives increased micronucleus (MN) frequency, suggesting the induction of chromosomal damage. In the antigenotoxicity assay, differential protective effects were observed depending on the mutagen used. Cotreatment with DXR demonstrated that (1) significantly reduced MN frequency at the highest tested concentration, whereas (3) and (4) significantly decreased DXR-induced chromosomal damage. When MMS was used as the mutagenic agent, (2) significantly reduced MN formation at lower concentrations. Taken together, these findings support a Janus-like behavior of 3-benzoylcoumarins and indicate dose-dependent genotoxic and antigenotoxic properties and highlight their potential as modulators of DNA damage induced by different mutagenic mechanisms. Overall, these findings highlight the concentration-dependent dual biological effects of 3-benzoylcoumarins and support further investigations into their potential as chemopreventive agents.