UK-2A, B, C and D, novel antifungal antibiotics from Streptomyces sp 517-02 - IV. Comparative studies of UK-2A with antimycin A(3) on cytotoxic activity and reactive oxygen species generation in LLC-PK1 cells

UK-2A, a novel antifungal antibiotic, is a structural relative of antimycin A, (AA) and its mode of action is similar to that of AA which inhibits mit ochondrial electron transport at complex III. In spite of their structural resemblance, AA had strong cytotoxicity while UK-2A had little cytotoxicity against LLC-PK1 cells as well as other types of cultured cells. When cells were treated with UK-2A or with AA the intracellular ATP content decreased significantly within 5 minutes in glucose-free medium to almost the same e xtent in both cases. Moreover, under the same conditions, UK-2A killed cell s at a similar rate to AA. This suggested that UK-2A entered into the cells and, like AA, inhibited mitochondrial electron transport. On the other han d, AA stimulated reactive oxygen species (ROS) production within 5 minutes even at a low concentration of 1 mu M whereas UK-2A did not show such an ef fect. The difference in the ROS-producing abilities of UK-2A and AA may acc ount for the different cytotoxic effects of the two compounds.