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Therapy

Trolox enhances the anti-lymphoma effects of arsenic trioxide, while protecting against liver toxicity

Leukemia volume 21, pages 2117–2127 (2007)Cite this article

Abstract

Arsenic trioxide (As2O3) is an effective therapy in acute promyelocytic leukemia (APL), but its use in other malignancies is limited by the higher concentrations required to induce apoptosis. We have reported that trolox, an analogue of α-tocopherol, increases As2O3-mediated apoptosis in a variety of APL, myeloma and breast cancer cell lines, while non-malignant cells may be protected. In the present study, we extended previous results to show that trolox increases As2O3-mediated apoptosis in the P388 lymphoma cell line in vitro, as evidenced by decrease of mitochondrial membrane potential and release of cytochrome c. We then sought to determine whether this combination can enhance antitumor effects while protecting normal cells in vivo. In BDF1 mice, trolox treatment decreased As2O3-induced hepatomegaly, markers of oxidative stress and hepatocellular damage. In P388 tumor-bearing mice, As2O3 treatment prolonged survival, and the addition of trolox provided a further significant increase in lifespan. In addition, the combination of As2O3 and trolox inhibited metastatic spread, and protected the tumor-bearing mice from As2O3 liver toxicity. Our results suggest, for the first time, that trolox might prevent some of the clinical manifestations of As2O3-related toxicity while increasing its pro-apoptotic capacity and clinical efficacy in hematological malignancies.

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Acknowledgements

We thank Dr Xiujie Li for assistance with histological analysis. We also thank Kathy Ann Forner, Veronique Michaud and Scott Hartigan for technical help with the animal model, and Dr Samuel Waxman for helpful discussions. This work was supported by grants from the Canadian Institutes of Health Research (CIHR) and the Samuel Waxman Cancer Research Foundation (to WH Miller Jr). WH Miller is a Chercheur National of the Fonds de la Recherche en Santé du Quebec (FRSQ). ZD is supported by student grant from the CIHR. KKM and AL are supported by fellowships from Montreal Centre for Experimental Therapeutics in Cancer (MCETC)/CIHR/FRSQ.

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Authors and Affiliations

  1. Segal Cancer Centre and Lady Davis Institute for Medical Research, McGill University, Montreal, Québec, Canada

    Z Diaz, A Laurenzana, K K Mann, T A Bismar & W H Miller Jr

  2. Department of Oncology, McGill University, Montreal, Québec, Canada

    Z Diaz, A Laurenzana, K K Mann, T A Bismar, H M Schipper & W H Miller Jr

  3. Department of Pathology, McGill University, Montreal, Québec, Canada

    T A Bismar

  4. Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada

    H M Schipper

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Correspondence to W H Miller Jr.

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Diaz, Z., Laurenzana, A., Mann, K. et al. Trolox enhances the anti-lymphoma effects of arsenic trioxide, while protecting against liver toxicity. Leukemia 21, 2117–2127 (2007). https://doi.org/10.1038/sj.leu.2404891

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