Apoptosis-inducing oxovanadium(IV) complexes of 1,10-phenanthroline against human ovarian cancer.
In a systematic effort to identify a potent anticancer agent against human ovarian cancer, we synthesized 15 oxovanadium(IV) complexes, and examined their cytotoxic activity against human ovarian cancer cell lines PA-1, SKOV-3, ES-2 and OVCAR-3 using a MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyletetrazolium bromide]-based assay. The apoptosis-inducing ability of the oxovanadium compounds was evaluated by the two-color flow cytometric terminal deoxynucleotidyl transferase-based assay that labels 3'-hydroxyl ends of fragmented DNA (TUNEL) assay and confocal laser scanning microscopy. Notably, all eight oxovanadium complexes of 1,10 phenanthroline exhibited significant cytotoxicity and induced apoptosis within 24 h. The mono-chelated, VO(NO2-phen) and bis-chelated, VO(Me2-phen)2, VO(Cl-phen)2 and VO(NO2-phen)2 complexes were the most potent oxovanadium compounds, and killed target cancer cells at low micromolar concentrations. The marked differences in the cytotoxic activity of oxovanadium(IV) complexes containing different heterocyclic ancillary ligands suggest that the cytotoxic activity of these compounds is determined by the identity of the five-member bidentate ligands, as well as the nature of the substituents on the heterocyclic aromatic rings. Our results presented herein provide experimental evidence that oxovanadium compounds induce apoptosis in human ovarian cancer cells. The lead compounds, VO(Me2-phen)2 and VO(NO2-phen)2, may be useful in the treatment of ovarian cancer.
D'Cruz
O J
OJ
Department of Reproductive Biology, Parker Hughes Institute, St Paul, MN 55113, USA.
Dong
Y
Y
Uckun
F M
FM
D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology*; D010618:Phenanthrolines / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014638:Vanadates / Q000138:chemical synthesis / Q000494:pharmacology*
D010618:Phenanthrolines; C075743:oxovanadium IV; D014638:Vanadates; C025205:1,10-phenanthroline