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Anti-tumoral effect of arsenic compound, sodium metaarsenite (KML001), in non-Hodgkin’s lymphoma: an in vitro and in vivo study

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Summary

Arsenic compounds have been used in traditional medicine for several centuries. KML001 (sodium metaarsenite; NaAsO2) is an orally bio-available arsenic compound with potential anti-cancer activity. However, the effect of KML001 has not been studied in lymphoid neoplasms. The aim of this study is to evaluate the anti-proliferative effect of KML001 in non-Hodgkin’s lymphoma and to compare its efficacy with As2O3. KML001 inhibited cellular proliferation in all tested lymphoma cell lines as well as JurkatR cells (adriamycin-resistant Jurkat cells) in a dose-dependent manner, while As2O3 was not effective. Cell cycle regulatory protein studies have suggested that KML001 induces G1 arrest via p27-induced inhibition of the kinase activities of CDK2, 4, and 6. Treatment of KML001 induced apoptosis in Jurkat and JurkatR cells. The apoptotic process was associated with down-regulation of Bcl-2 (antiapoptotic molecule), up-regulation of Bax (proapoptotic molecule), and inhibition of caspase-3, -8, and -9. In addition, cell signaling including the STAT, PI3K/Akt, MAPK, and NF-κB signal pathways were inhibited in KML001-treated Jurkat and JurkatR cells. Furthermore, targeting the telomere by KML001 was observed in the Jurkat and JurkatR cells. The In vivo anti-tumoral activity of KML001 was confirmed in a xenograft murine model. Interestingly, partial responses were seen in two lymphoma patients treated with 10 mg/day (follicular lymphoma for 16 weeks and mantle cell lymphoma for 24 weeks) without severe toxicities. These findings suggest that KML001 may be a candidate agent for the treatment of de novo, refractory, and relapsed non-Hodgkin’s lymphoma patients.

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Acknowledgments

The present study was conducted at Hanyang University Hospital Clinical Laboratory and Seoul National University College of Pharmacy, and this work was supported by Komipharm International Co., Ltd., Seoul, Korea.

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Authors and Affiliations

  1. Division of Hematology, Department of Internal Medicine, Hanyang University College of Medicine, 17 Haengdang-dong, Sungdong-ku, Seoul, 133-792, South Korea

    Jin Sun Yoon, Deok Won Hwang, Eun Shil Kim, Jung Soon Kim, Jun Ho Yi, Jieun Uhm, Young Woong Won, Byeong Bae Park, Jung Hye Choi & Young Yiul Lee

  2. Pharmaceutical Division, Komipharm International Co., Ltd., Seoul, South Korea

    Sujong Kim

  3. Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea

    Sujong Kim

  4. College of Pharmacy, Seoul National University, Seoul, South Korea

    Hwa Jin Chung & Sang Kook Lee

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  1. Jin Sun Yoon
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Correspondence to Young Yiul Lee.

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The authors disclose no potential conflicts of interest.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional Review Board of Hanyang University Hospital and in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

All procedures performed in studies involving animals were in accordance with the ethical standards of Seoul National University.

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Yoon, J.S., Hwang, D.W., Kim, E.S. et al. Anti-tumoral effect of arsenic compound, sodium metaarsenite (KML001), in non-Hodgkin’s lymphoma: an in vitro and in vivo study. Invest New Drugs 34, 1–14 (2016). https://doi.org/10.1007/s10637-015-0301-z

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  • DOI: https://doi.org/10.1007/s10637-015-0301-z

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