Induction of apoptosis in human leukemia cells through the production of reactive oxygen species and activation of HMOX1 and Noxa by benzene, toluene, and o-xylene.

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Sarma SN, Kim YJ, Song M, Ryu JC

Induction of apoptosis in human leukemia cells through the production of reactive oxygen species and activation of HMOX1 and Noxa by benzene, toluene, and o-xylene.

Toxicology. 2011 Feb 27;280(3):109-17. doi: 10.1016/j.tox.2010.11.017. Epub 2010 Dec 7.

PubMed ID
21144877 [ View in PubMed
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Abstract

Whereas benzene (BZ) is a well-known human carcinogen, toluene (TOL) and o-xylene (o-XY) are not; however, all three compounds are important environmental pollutants. Although BZ, TOL, and o-XY have been shown to induce apoptosis in vitro, their mechanism of toxicity remains unclear. In this study, we sought to identify the apoptotic pathway(s) activated by BZ, TOL, and o-XY in human HL-60 promyelocytic leukemia cells. Cell cycle analysis by propidium iodide (PI) staining and flow cytometric analyses of Annexin V/PI double-stained cells revealed similar patterns of apoptosis following BZ, TOL, and o-XY exposure. Though reactive oxygen species (ROS) production contributes significantly to BZ metabolite-induced apoptotic cell death, we hypothesized that BZ, TOL, and o-XY can themselves trigger ROS production, leading to the activation of apoptotic signaling. Dose-dependent increases in ROS production and significant tail moments were observed in HL-60 cells exposed to all three compounds. Real-time RT-PCR revealed increased HMOX1 and Noxa expression in BZ-, TOL-, and o-XY-treated HL-60 cells, confirming the results of previous microarray analyses. Similar expression profiles were found in human K562 erythromyeloblastoid leukemia cells and human U937 leukemic monocyte lymphoma cells. Pretreatment with the ROS scavenger N-acetyl cysteine decreased the effects of exposure to BZ, TOL, and o-XY. In summary, this study provides useful insights into the mechanism of BZ-, TOL-, and o-XY-induced apoptosis in leukemia cells.