Mechanism of the cytotoxicity of the diazoparaquinone antitumor antibiotic kinamycin F.
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.
O'Hara
Kimberley A
KA
Faculty of Pharmacy, University of Manitoba, 50 Sifton Road, Winnipeg, Manitoba, Canada R3T 2N2.
Wu
Xing
X
Patel
Daywin
D
Liang
Hong
H
Yalowich
Jack C
JC
Chen
Nan
N
Goodfellow
Valerie
V
Adedayo
Otunola
O
Dmitrienko
Gary I
GI
Hasinoff
Brian B
BB
D000640:Amitrole / Q000494:pharmacology; D000951:Antigens, Neoplasm; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D004229:Dithiothreitol / Q000737:chemistry; D004357:Drug Synergism; D004578:Electron Spin Resonance Spectroscopy; D005452:Fluoresceins / Q000378:metabolism; D005978:Glutathione / Q000737:chemistry / Q000494:pharmacology; D006735:Horseradish Peroxidase / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D020014:K562 Cells; D011809:Quinones / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D059005:Topoisomerase II Inhibitors; D000095602:Angucyclines and Angucyclinones
D000640:Amitrole; D000951:Antigens, Neoplasm; D004247:DNA; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D004229:Dithiothreitol; D005452:Fluoresceins; D005978:Glutathione; D006735:Horseradish Peroxidase; D006861:Hydrogen Peroxide; D011809:Quinones; D059005:Topoisomerase II Inhibitors; C029569:diacetyldichlorofluorescein; C059021:kinamycin F; D000095602:Angucyclines and Angucyclinones