Abstract |
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.
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Authors | L Yin, T Ohno, R Weichselbaum, S Kharbanda, D Kufe |
Journal | Molecular cancer therapeutics
(Mol Cancer Ther)
Vol. 1
Issue 1
Pg. 43-8
(Nov 2001)
ISSN: 1535-7163 [Print] United States |
PMID | 12467237
(Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Antineoplastic Agents
- CDKN1A protein, human
- Coumarins
- Cyclin-Dependent Kinase Inhibitor p21
- Cyclins
- Isocoumarins
- Reactive Oxygen Species
- Tumor Suppressor Protein p53
- isocoumarin NM-3
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Topics |
- Antineoplastic Agents
(toxicity)
- Apoptosis
(drug effects)
- Cell Cycle
(drug effects)
- Cell Death
- Coumarins
(toxicity)
- Cyclin-Dependent Kinase Inhibitor p21
- Cyclins
(metabolism)
- Down-Regulation
- Female
- Humans
- Immunoblotting
- Isocoumarins
- Necrosis
- Reactive Oxygen Species
(metabolism)
- Tumor Cells, Cultured
(drug effects, metabolism, pathology)
- Tumor Suppressor Protein p53
(metabolism)
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