isocoumarin-nm-3 and Necrosis

2-(8-Hydroxy-6-methoxy-1-oxo-1H-2-benzopyran-3-yl) propionic acid (NM-3) is an isocoumarin derivative that has recently entered clinical trials for evaluation as a p.o.-bioavailable, antiangiogenic molecule. NM-3 induces endothelial cell death at low microM concentrations by a nonapoptotic mechanism. The present studies have assessed the direct effects of NM-3 on human carcinoma cells. The results demonstrate that NM-3 treatment is associated with the generation of reactive oxygen species and loss of clonogenic survival. In concert with these findings, we show that exposure to NM-3 is associated with increases in expression of the p53 tumor suppressor. In human MCF-7 and ZR-75-1 breast cancer cells, NM-3 induces the p21 cyclin-dependent kinase inhibitor, cell cycle arrest at G1-S-phase, and necrotic cell death. Moreover, human PA-1 ovarian carcinoma and HeLa cervical carcinoma cells respond to NM-3 with the induction of apoptosis by a reactive oxygen species-dependent mechanism. These findings demonstrate that NM-3 has direct effects on carcinoma cells at clinically achievable concentrations and that this agent could be effective in targeting both the tumor and its vasculature.

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Death; Coumarins; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Down-Regulation; Female; Humans; Immunoblotting; Isocoumarins; Necrosis; Reactive Oxygen Species; Tumor Cells, Cultured; Tumor Suppressor Protein p53