The Potential Role of Topoisomerase II Inhibition in Hydroquinone-Induced Alterations in the Maturation of Mouse Myeloblasts

Abstract

The mechanism by which exposure to the industrial solvent benzene (BZ) can result in aplastic anemia or leukemia (see Snyder and Kalf, 1994 for review) has been under intensive investigation. Topoisomerase (topo) II inhibitors are used clinically as cancer chemotherapeutic agents and can also lead to secondary AML (see Felix, 1998; Leone et al., 1999 for review). Hydroquinone (HQ), a hematotoxic metabolite of BZ, has been shown to inhibit purified human topo II (Hutt and Kalf, 1996; Frantz et al., 1996). It has therefore been suggested that some of the hematotoxic effects of BZ may be mediated by the ability of some of its metabolites to inhibit topo II activity (Whysner, 2000). In the studies presented here a normal, IL-3 dependent mouse myeloblast cell line (32D.3 (G)) was used to determine whether the hematotoxic effects of BZ may result from inhibition of topo II by HQ. The 32D.3 (G) myeloblasts undergo differentiation and maturation to neutrophils upon treatment with the physiological inducer, granulocyte colony-stimulating factor (G-CSF) (Metcalf, 1985; Valtieri et al., 1987). In this system HQ treatment inhibits apoptosis, induces differentiation of myeloblasts to the myelocyte stage, and blocks maturation to the neutrophil (Hazel et al., 1995), a series of events similar to those observed in AML, which is characterized by clonal expansion of immature granulocytes (Lowenberg and Delwel, 1991). There is evidence linking topo II activity to differentiation and maturation in the HL-60, human leukemia cell line. In this system 3-nitrobenzothiazolo[3,2-a]quinolinium, an inhibitor of topo II activity, has been shown to induce incomplete myeloid differentiation (Baez and Sepulveda, 1992).