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MER1, a novel organic arsenic derivative, has potent PML-RARα- independent cytotoxic activity against leukemia cells

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Summary

Arsenic trioxide (ATO) is an inorganic arsenic derivative that is highly effective against PML-RARα-positive leukemia but much less against other hematological malignancies. We synthesized an organic arsenic derivative (OAD), S-dimethylarsino-thiosuccinic acid (MER1), which offers a superior toxicity profile and comparable in vitro activity relative to ATO. In Swiss Webster mice, maximally-tolerated cumulative dose of MER1 when given IV for 5 days was 100 mg/kg/d. We demonstrated that MER1 induced apoptosis and dose- and time-dependent inhibition of survival and growth in a panel of myeloid leukemia cell lines. Unlike ATO, this activity was independent of PML-RARα status and was not associated with induction of myeloid maturation. In NB4 and HL60 cells, MER1 and ATO induced caspase activation and dissipation of mitochondrial transmembrane potential. At the same time, MER1 induced generation of reactive oxygen species (ROS) and cell cycle arrest in G2/M phase and proved to be more potent than ATO at inducing apoptosis. ROS generation and intracellular glutathione levels were key modulators of MER1-induced cytotoxicity as evidenced by abrogation of apoptosis in myeloid leukemia cell lines pretreated with the disulfide bond-reducing agent dithiothreitol or the radical scavenger N-acetyl-L-cysteine. Collectively, these data indicate that MER1 induces apoptosis in PML-RARα-positive and -negative myeloid leukemia cells by enhancing oxidative stress. This agent, therefore, combines low in vivo toxicity with formidable in vitro pro-apoptotic ROS-mediated activity, and may represent a novel OAD suitable for clinical development against a variety of hematological malignancies.

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Acknowledgement

Robert A. Welch Foundation sponsored work done by RAZ.

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Authors and Affiliations

  1. Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Unit 428, 1515 Holcombe Blvd., Houston, TX, 77030, USA

    Mirna Golemovic, Alfonso Quintás-Cardama, Taghi Manshouri, Nada Orsolic, Hatice Duzkale, Emil J. Freireich, Hagop Kantarjian & Srdan Verstovsek

  2. Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    Mary Johansen

  3. Department of Chemistry, Texas A&M University, College Station, TX, USA

    Ralph A. Zingaro

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  1. Mirna Golemovic
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  2. Alfonso Quintás-Cardama
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  3. Taghi Manshouri
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Correspondence to Srdan Verstovsek.

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Suppl. Fig. 1

NB4 cells were treated for 24 h with ATO (lanes 1–4) or MER1 (lanes 5–8) at 0.5 μM, 1, 5 μM, and 10 μM, respectively. Degradation of Bcl-2 protein was observed by immunoprecipitation after ATO (but not MER1) treatment. Bcl-2 expression in untreated NB4 cells is presented in lane 9. (PPT 238 kb)

Suppl. Fig. 2

HL60 cells were treated with MER1 (5 μM) alone or in combination with NAC (10 mM) for 8 h, 14 h, or 24 h. The percentage of cells in G2/M phase were detected by flow cytometry. The appropriate controls with only 10 mM NAC added were prepared as well. They did not differ from displayed non-treated controls. (PPT 148 kb)

Suppl. Fig. 3

MER1 treatment is not associated with telomere shortening. Contour plots showing PNA probe fluorescence versus DNA content in: (A) NB4 and CEM-1301 cells; (B) NB4 cells cultured in the presence of ATO 1 μM and CEM-1301 cells; (C) NB4 cells cultured in the presence of MER1 1 μM and CEM-1301 cells. (PPT 85 kb)

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Golemovic, M., Quintás-Cardama, A., Manshouri, T. et al. MER1, a novel organic arsenic derivative, has potent PML-RARα- independent cytotoxic activity against leukemia cells. Invest New Drugs 28, 402–412 (2010). https://doi.org/10.1007/s10637-009-9267-z

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