SU5416 sensitizes ovarian cancer cells to cisplatin through inhibition of nucleotide excision repair.
SU5416 is reported to be a selective inhibitor of vascular endothelial growth factor, and it has metwith limited success in the clinic. In the present study, we investigated whether SU5416 could augment cisplatin-induced cytotoxicity in human ovarian cancer cells. When used as a single agent, 2-h exposures to SU5416 were not harmful to the cells up to doses of 100 microM. For 48-h exposures, the SU5416 IC20 and IC50 were 17 and 34 microM, respectively. When used with cisplatin, the effect of SU5416 was sequence dependent. SU5416 given first was subadditive, whereas cisplatin given first was supraadditive. Cisplatin was given as a 1-h exposure. Augmented cisplatin cytotoxicity was seen with 2-h exposures to SU5416 at doses of 17-34 microM. This was associated with a decrease in cisplatin-DNA adduct repair, as measured by atomic absorbance spectrometry. Treatment of the ovarian carcinoma cells with SU5416 was also associated with a reduced expression of ERCC-1 protein and c-jun mRNA, as well as a decrease in c-Jun and JNK activities. We conclude that SU5416 can be used to augment cisplatin-induced cell killing at doses that are non-toxic. This effect may occur through direct or indirect reduction of the activity of AP-1 and DNA repair.
Zhong
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The Mary Babb Randolph Cancer Center, Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Robert C. Byrd Health Sciences Center, PO Box 9300, Morgantown, West Virginia 26506, USA.
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D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism; D002945:Cisplatin / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects*; D004268:DNA-Binding Proteins; D004720:Endonucleases; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011506:Proteins / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000187:drug effects; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007211:Indoles; D011506:Proteins; D016755:Proto-Oncogene Proteins c-jun; D011758:Pyrroles; D018808:Transcription Factor AP-1; C116890:Semaxinib; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; C071447:ERCC1 protein, human; D004720:Endonucleases; D002945:Cisplatin