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Cytogenetics

Arsenic trioxide (As2O3)-induced apoptosis and differentiation in retinoic acid-resistant acute promyelocytic leukemia model in hGM-CSF-producing transgenic SCID mice

Leukemia volume 14, pages 431–438 (2000)Cite this article

Abstract

Recent clinical studies in China and USA showed that arsenic trioxide (As2O3) is an effective treatment of acute promyelocytic leukemia (APL) patients refractory to all-trans retinoic acid (RA). We here investigate the effects of As2O3on RA-resistant APL in vivo and in vitro using our RA-resistant APL model system. As2O3 can induce inhibition of cellular growth of both RA-sensitive NB4 and RA-resistant UF-1 APL cells via induction of apoptosis in vitro. The expression of BCL-2 protein decreased in a dose- and time-dependent manner in NB4 cells. Interestingly, the levels of BCL-2 protein were not modulated by As2O3, but it did upregulate BAX protein in UF-1 cells. UF-1 cells (1 × 107) were transplanted into hGM-CSF-producing transgenic SCID mice and successfully formed subcutaneous tumors. After 40 days of implantation, mice were treated with As2O3, all-trans RA and PBS for 21 days. In all-trans RA- and PBS-treated mice, tumors grew rapidly, with a 4.5-fold increase in volume at day 21 compared to the initial size. In marked contrast, tumor size was decreased to half of the initial size by the treatment of As2O3, which resulted in cells with the typical appearance of apoptosis. Interestingly, one of the As2O3-treated mice showed mature granulocytes in the diminished tumor, suggesting that As2O3 had dual effects on RA-resistant APL cells in vivo: both inducing apoptosis and differentiation of the leukemic cells. We conclude that our RA-resistant APL model will be useful for evaluating novel therapeutic approaches to patients with RA-resistant APL, and for further investigation of the metabolism of As2O3 in vivo.

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Acknowledgements

This work was supported by grants from the Ministry of Education, Science and Culture in Japan, the Special Cordination Funds for promoting Science and Technology of the Science and Technology Agency of the Japanese Government and the National Grant-in-Aid for the Establishment of a High Tech Research Center in a Private University.

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Authors and Affiliations

  1. Department of Internal Medicine, Division of Hematology, Keio University School of Medicine, Tokyo, Japan

    K Kinjo, M Kizaki, A Muto, Y Fukuchi & Y Ikeda

  2. Department of Pathology, Division of Hematology, Keio University School of Medicine, Tokyo, Japan

    Y Fukuchi & M Ito

  3. Central Institute for Experimental Animals, Kanagawa, Japan

    A Umezawa & J Hata

  4. Department of Molecular and Cellular Oncology/Microbiology, Faculty of Dentistry, Tokyo Medical and Dental University, Tokyo, Japan

    K Yamato

  5. Division of Oral Science, The National Institute of Infectious Disease, Tokyo, Japan

    T Nishihara

  6. Department of Pathology, School of Medicine, Tokai University, Kanagawa, Japan

    Y Ueyama

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Kinjo, K., Kizaki, M., Muto, A. et al. Arsenic trioxide (As2O3)-induced apoptosis and differentiation in retinoic acid-resistant acute promyelocytic leukemia model in hGM-CSF-producing transgenic SCID mice. Leukemia 14, 431–438 (2000). https://doi.org/10.1038/sj.leu.2401646

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