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Arsenic trioxide (As2O3) gradually downregulates tissue factor expression without affecting thrombomodulin expression in acute promyelocytic leukemia cells

Leukemia volume 14, pages 941–943 (2000)Cite this article

Arsenic trioxide (As2O3) was shown to induce complete remission in a high proportion of patients with relapsed and all-trans retinoic acid (ATRA)-resistant acute promyelocytic leukemia (APL).1 The clinical response to As2O3 is associated with the induction of nonterminal cytodifferentiation and the activation of cysteine proteases (caspases) that are characteristic of apoptosis. We have recently found that vitamin A derivatives, retinoids such as ATRA, exert anticoagulant effects by upregulating thrombomodulin (TM) and downregulating tissue factor (TF) expression in APL and acute monoblastic leukemia cells.23 The effect of ATRA explains the rapid improvement of disseminated intravascular coagulation syndrome (DIC), which is a complication, observed in almost all APL patients. Since the mechanism of action of As2O3 does not involve its binding to retinoic acid receptors (RARs), in contrast to that of retinoic acids (RAs),4 we have examined the regulation of TM and TF expression in APL cell line, NB4 cells treated with As2O3 alone or in combination with ATRA. Our data generally support a very recent report by Zhu et al,5 which has appeared in this journal.

After we began treating NB4 cells with As2O3, we replaced half of NB4 cell-suspended medium by fresh medium containing 10% fetal calf serum and 1 μM As2O3 every 3 days. Such a culture condition avoids serum starvation, makes cells more resistant to apoptosis induced by As2O3 and keeps cell concentration rather more constant than that previously reported in studies in vitro. Treatment of NB4 cells with 1 μM As2O3 for 14 days induced morphological changes, such as condensed chromatin, smaller nuclei, a decreased nuclei/cytoplasm ratio, and the appearance of granules in the cytoplasm. About 30% of the cells were found to resemble myelocyte morphologically, and the maturation stage of the remainder of the cells still corresponded to the promyelocyte stage. Less than 10% of total cells appeared apoptotic showing nuclear fragmentation. More than 90% of cells still kept alive by Trypan blue exclusion method. Viable cell numbers were counted and adjusted.

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Acknowledgements

This work was supported in part by research grants from the Atsuko Ouchi Memorial Fund, Tokyo Medical and Dental University, from the Research Foundation for Clinical Pharmacology.

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  1. School of Allied Health Sciences, Tokyo Medical and Dental University, Tokyo, Japan

    M Ohsawa, T Koyama, M Shibakura & S Kamei

  2. First Department of Internal Medicine, Tokyo Medical and Dental University, Tokyo, Japan

    S Hirosawa

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Ohsawa, M., Koyama, T., Shibakura, M. et al. Arsenic trioxide (As2O3) gradually downregulates tissue factor expression without affecting thrombomodulin expression in acute promyelocytic leukemia cells. Leukemia 14, 941–943 (2000). https://doi.org/10.1038/sj.leu.2401755

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