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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. This Article Full Text (PDF) All Versions of this Article: 2004-05-1772v1 105/3/1237    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Diaz, Z. Articles by Miller Jr, W. H Search for Related Content PubMed PubMed Citation Articles by Diaz, Z. Articles by Miller Jr, W. H Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 7, 2004 Accepted September 14, 2004 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 S Bohle, Hyman M Schipper, and Wilson H Miller Jr* Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada Department of Chemistry, McGill University, Montreal, Quebec, Canada * Corresponding author; email: wmiller{at}ldi.jgh.mcgill.ca. 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 HO-1 protein levels, 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 non-malignant 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J.-H. Lee, H.-N. Kim, D. Yang, K. Jung, H.-M. Kim, H.-H. Kim, H. Ha, and Z. H. Lee Trolox Prevents Osteoclastogenesis by Suppressing RANKL Expression and Signaling J. Biol. Chem., May 15, 2009; 284(20): 13725 - 13734. [Abstract] [Full Text] [PDF] L. J. Hoffer, M. Levine, S. Assouline, D. Melnychuk, S. J. Padayatty, K. Rosadiuk, C. Rousseau, L. Robitaille, and W. H. Miller Jr Phase I clinical trial of i.v. ascorbic acid in advanced malignancy Ann. Onc., November 1, 2008; 19(11): 1969 - 1974. [Abstract] [Full Text] [PDF] P. Lunghi, N. Giuliani, L. Mazzera, G. Lombardi, M. Ricca, A. Corradi, A. M. Cantoni, L. Salvatore, R. Riccioni, A. Costanzo, et al. Targeting MEK/MAPK signal transduction module potentiates ATO-induced apoptosis in multiple myeloma cells through multiple signaling pathways Blood, September 15, 2008; 112(6): 2450 - 2462. [Abstract] [Full Text] [PDF] K. K. Mann, M. Colombo, and W. H. Miller Jr. Arsenic trioxide decreases AKT protein in a caspase-dependent manner Mol. Cancer Ther., June 1, 2008; 7(6): 1680 - 1687. [Abstract] [Full Text] [PDF] J. Lu, E.-H. Chew, and A. Holmgren Targeting thioredoxin reductase is a basis for cancer therapy by arsenic trioxide PNAS, July 24, 2007; 104(30): 12288 - 12293. [Abstract] [Full Text] [PDF] W. Yang, J. Ge, H. Liu, K. Zhao, X. Liu, X. Qu, W. Li, Y. Huang, A. Sun, and Y. Zou Arsenic trioxide eluting stent reduces neointima formation in a rabbit iliac artery injury model Cardiovasc Res, December 1, 2006; 72(3): 483 - 493. [Abstract] [Full Text] [PDF] P. Lunghi, A. Costanzo, L. Salvatore, N. Noguera, L. Mazzera, A. Tabilio, F. Lo-Coco, M. Levrero, and A. Bonati MEK1 inhibition sensitizes primary acute myelogenous leukemia to arsenic trioxide-induced apoptosis Blood, June 1, 2006; 107(11): 4549 - 4553. [Abstract] [Full Text] [PDF] S. Assouline and W. H. Miller High-dose vitamin C therapy: renewed hope or false promise? Can. Med. Assoc. J., March 28, 2006; 174(7): 956 - 957. [Full Text] [PDF]

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