Details

Autor(en) / Beteiligte

• O'Hara, Kimberley A.
• Wu, Xing
• Patel, Daywin
• Liang, Hong
• Yalowich, Jack C.
• Chen, Nan
• Goodfellow, Valerie
• Adedayo, Otunola
• Dmitrienko, Gary I.
• Hasinoff, Brian B.

Titel

Mechanism of the cytotoxicity of the diazoparaquinone antitumor antibiotic kinamycin F

Ist Teil von

• Free radical biology & medicine, 2007-10, Vol.43 (8), p.1132-1144

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2007

Quelle

MEDLINE

Beschreibungen/Notizen

• The bacterial metabolite kinamycin F, which is being investigated as a potent antitumor agent, contains an unusual and potentially reactive diazo group, a paraquinone, and a phenol functional group. Kinamycin F reacted with glutathione (GSH) in a complex series of reactions which suggested that kinamycin F may have its cytotoxicity modulated by GSH. Consistent with this idea, 2-oxo-4-thiazolidinecarboxylic acid treatment to increase cellular GSH levels and buthionine sulfoximine treatment to decrease GSH levels resulted in decreased and increased kinamycin F cytotoxicity, respectively, in K562 leukemia cells. Kinamycin F weakly bound to DNA and induced DNA damage in K562 cells that was independent of GSH levels. The GSH-promoted DNA nicking induced by kinamycin F in vitro was attenuated by deferoxamine, dimethyl sulfoxide, and catalase, which indicated that DNA damage initiated by this agent occurred in an iron-, hydrogen-peroxide-, and hydroxyl-radical-dependent manner. Electron paramagnetic resonance spectroscopy experiments showed that the GSH/kinamycin F system produced a semiquinone free radical and that the hydrogen peroxide/peroxidase/kinamycin F system generated a phenoxyl free radical. In conclusion, the results indicated that kinamycin F cytotoxicity may be due to reductive and/or peroxidative activation to produce DNA-and protein-damaging species.