Anti-tumoral effect of arsenic compound, sodium metaarsenite (KML001), in non-Hodgkin's lymphoma: an in vitro and in vivo study
- Authors
- Yoon, Jin Sun; Hwang, Deok Won; Kim, Eun Shil; Kim, Jung Soon; Kim, Sujong; Chung, Hwa Jin; Lee, Sang Kook; Yi, Jun Ho; Uhm, Jieun; Won, Young Woong; Park, Byeong Bae; Choi, Jung Hye; Lee, Young Yiul
- Issue Date
- Feb-2016
- Publisher
- SPRINGER
- Keywords
- Non-Hodgkin' s lymphoma; Sodium meta-arsenite; KML001; Cell signal; Telomere
- Citation
- INVESTIGATIONAL NEW DRUGS, v.34, no.1, pp.1 - 14
- Indexed
- SCIE
SCOPUS
- Journal Title
- INVESTIGATIONAL NEW DRUGS
- Volume
- 34
- Number
- 1
- Start Page
- 1
- End Page
- 14
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/5655
- DOI
- 10.1007/s10637-015-0301-z
- ISSN
- 0167-6997
- Abstract
- 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-kappa B 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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