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Blood, 1 February 2005, Vol. 105, No. 3, pp. 1237-1245.
Prepublished online as a Blood First Edition Paper on October 5, 2004; DOI 10.1182/blood-2004-05-1772.
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NEOPLASIA
Trolox selectively enhances arsenic-mediated oxidative stress and apoptosis in APL and other malignant cell lines
Zuanel Diaz,
Myrian Colombo,
Koren K. Mann,
Haixiang Su,
Kamilah N. Smith,
D. Scott Bohle,
Hyman M. Schipper, and
Wilson H. Miller, Jr
From the Lady Davis Institute for Medical Research, McGill University, Montreal, QC; and the Department of Chemistry, McGill University, Montreal, QC.
Although arsenic trioxide (As2O3) is an effective therapy in acute promyelocytic leukemia (APL), its use in other malignancies is limited by the toxicity of concentrations required to induce apoptosis in non-APL tumor cells. We looked for agents that would synergize with As2O3 to induce apoptosis in malignant cells, but not in normal cells. We found that trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), a widely known antioxidant, enhances As2O3-mediated apoptosis in APL, myeloma, and breast cancer cells. Treatment with As2O3 and trolox increased intracellular oxidative stress, as evidenced by heme oxygenase-1 (HO-1) protein levels, c-Jun terminal kinase (JNK) activation, and protein and lipid oxidation. The synergistic effects of trolox may be specific to As2O3, as trolox does not add to toxicity induced by other chemotherapeutic drugs. We explored the mechanism of this synergy using electron paramagnetic resonance and observed the formation of trolox radicals when trolox was combined with As2O3, but not with doxorubicin. Importantly, trolox protected nonmalignant cells from As2O3-mediated cytotoxicity. Our data provide the first evidence that trolox may extend the therapeutic spectrum of As2O3. Furthermore, the combination of As2O3 and trolox shows potential specificity for tumor cells, suggesting it may not increase the toxicity associated with As2O3 monotherapy in vivo.
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