The novel isocoumarin 2-(8-hydroxy-6-methoxy-1-oxo-1H-2-benzopyran-3-yl) propionic acid (NM-3) induces lethality of human carcinoma cells by generation of reactive oxygen species.
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.
Yin
L
L
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Ohno
T
T
Weichselbaum
R
R
Kharbanda
S
S
Kufe
D
D
D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death; D003374:Coumarins / Q000633:toxicity*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D006801:Humans; D015151:Immunoblotting; D049934:Isocoumarins; D009336:Necrosis; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D003374:Coumarins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D049934:Isocoumarins; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; C453300:isocoumarin NM-3