Inhibition of topoisomerases by fredericamycin A

Abstract

Fredericamycin is an antibiotic product of Streptomyces griseus that exhibits modest antitumor activity in vivo and in vitro. Because of its unique structure and the absence of a clearly defined mechanism of action, we examined the effects of this compound on L1210 cells in culture as well as on several enzymes that bind to DNA. Fredericamycin exhibits an IC50 of 4.4 microM toward L1210 cells, and its cytotoxicity is a function of the time of exposure as well as drug dose. No DNA breakage was observed in L1210 cells or isolated nuclei following exposure to highly lethal concentrations of fredericamycin. As a first step toward understanding its mechanism of action, we examined the effect of fredericamycin on several enzymes involved in DNA metabolism. The catalytic activity of both DNA topoisomerases I and II were totally inhibited by fredericamycin concentrations of 4.4 and 7.4 microM, respectively. Fredericamycin blocked etoposide-stimulated DNA cleavage by topoisomerase II both in vitro and in isolated nuclei. In addition, the drug inhibits DNA polymerase a in vitro, exhibiting an IC50 of 93 microM. These diverse actions of fredericamycin do not enable us to draw conclusions regarding its mechanism of antitumor effect but clearly identify it as a compound of pharmacologic interest.

Drug-induced apoptosis in yeast

“…Other successful antitumour drugs take advantage of the inhibition of topoisomerases, key enzymes in DNA transcription and replication. Fredericamycin A (FMA), an antibiotic product of Streptomyces griseus, camptothecin, an alkaloid derived from the plant Camptotheca acuminate and etoposide, a derivative of the podophyllotoxin from Podophyllum peltatum are among the antitumour drugs known to induce apoptosis in mammalian cells due to the inhibition of topoisomerases [82][83][84][85][86]. Although the induction of apoptosis in yeast cells by those drugs is not supported by the available data, some lines of evidence do support a link.…”

Synthesis and Biological Evaluation of Kibdelone C and Its Simplified Derivatives

“…43 To explore this possibility, methyl kibdelone C ( 57 ) was incubated with topoisomerase I and supercoiled DNA (Sc DNA). Topoisomerase I relaxes supercoiled DNA by introducing single-strand DNA breaks, allowing the cleaved strand to unwind, and rejoining the DNA fragments.…”

Fredericamycin A Affects Mitochondrial Inheritance and Morphology inSaccharomyces cerevisiae

“…1) Earlier studies suggest that it can act by spontaneously forming on oxidized free radical, with subsequent electron transfer to molecular oxygen, 2) but, biological evidence supporting this hypothesis has not been shown. Lathman et al reported that FMA inhibits in vitro activity of topoisomerases I and II and DNA polymerase , 3) however, the mechanism of action of the drug in vivo is obscure.…”