Trolox selectively enhances arsenic-mediated oxidative stress and apoptosis in APL and other malignant cell lines.
Although arsenic trioxide (As(2)O(3)) 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 As(2)O(3) 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 As(2)O(3)-mediated apoptosis in APL, myeloma, and breast cancer cells. Treatment with As(2)O(3) 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 As(2)O(3), 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 As(2)O(3), but not with doxorubicin. Importantly, trolox protected nonmalignant cells from As(2)O(3)-mediated cytotoxicity. Our data provide the first evidence that trolox may extend the therapeutic spectrum of As(2)O(3). Furthermore, the combination of As(2)O(3) and trolox shows potential specificity for tumor cells, suggesting it may not increase the toxicity associated with As(2)O(3) monotherapy in vivo.
Lady Davis Institute for Medical Research,McGill University, Montreal, QC, Canada.
Zuanel
Z
Diaz
Myrian
M
Colombo
Koren K
KK
Mann
Haixiang
H
Su
Kamilah N
KN
Smith
D Scott
DS
Bohle
Hyman M
HM
Schipper
Wilson H
WH
Miller
D017304:Annexin A5 / Q000032:analysis; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001151:Arsenic / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002839:Chromans / Q000494:pharmacology*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute; D008565:Membrane Proteins; D018384:Oxidative Stress / Q000187:drug effects*
D017304:Annexin A5; D000975:Antioxidants; D002839:Chromans; D008565:Membrane Proteins; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D048031:JNK Mitogen-Activated Protein Kinases; D001151:Arsenic; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid