Analysis of hemin-induced protection of human hemopoietic cells from the cytotoxic effects of anthracyclines.
Experiments were performed with K562 erythroleukemia cells to further characterize the observation that hemin protects hemopoietic cells from the cytotoxic effects of anthracycline drugs. The present studies demonstrate that this protective effect of hemin applies only to anthracyclines and not to other classes of antineoplastic agents. Hemin interferes with the cellular accumulation of various anthracyclines, as measured by cytofluorography, and prevents binding of anthracyclines to isolated cell nuclei. Exposure of K562 cells to hemin retards the anthracycline-induced arrest of cells at the G2-M interphase of the cell cycle and permits cells to undergo continuing division as demonstrated by clonal growth in plasma clot cultures. Furthermore, hemin decreases the ability of anthracyclines to unwind simian virus 40 supercoiled DNA in vitro. The protective effect of hemin fails to occur if cells have been preincubated with this agent for 72 h before they are exposed to Adriamycin in the absence of hemin. The findings suggest that hemin prevents anthracycline-induced cytotoxicity by acting at several levels. These effects may be mediated by direct interactions of hemin with DNA and perhaps other cellular constituents or by molecular complex formation between hemin and anthracyclines at intracellular sites.
Tsiftsoglou
A S
AS
Charles A. Dana Research Institute, Department of Medicine, Beth Israel Hospital-Harvard Medical School, Boston, Massachusetts 02215.
Wong
W
W
Robinson
S H
SH
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000633:toxicity; D001692:Biological Transport / Q000187:drug effects; D002451:Cell Compartmentation / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006418:Heme / Q000031:analogs & derivatives*; D006427:Hemin / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D009279:Naphthacenes / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D009279:Naphthacenes; D006418:Heme; D006427:Hemin; D004247:DNA