title: Anti-tumoral effect of arsenic compound, sodium metaarsenite (KML001), in non-Hodgkin's lymphoma: an in vitro and in vivo study.
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-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.
authors.affiliation: Division of Hematology, Department of Internal Medicine, Hanyang University College of Medicine, 17 Haengdang-dong, Sungdong-ku, Seoul, 133-792, South Korea.
authors.forename: Jin Sun
authors.initials: JS
authors.lastname: Yoon
authors.affiliation: Division of Hematology, Department of Internal Medicine, Hanyang University College of Medicine, 17 Haengdang-dong, Sungdong-ku, Seoul, 133-792, South Korea.
authors.forename: Deok Won
authors.initials: DW
authors.lastname: Hwang
authors.affiliation: Division of Hematology, Department of Internal Medicine, Hanyang University College of Medicine, 17 Haengdang-dong, Sungdong-ku, Seoul, 133-792, South Korea.
authors.forename: Eun Shil
authors.initials: ES
authors.lastname: Kim
authors.affiliation: Division of Hematology, Department of Internal Medicine, Hanyang University College of Medicine, 17 Haengdang-dong, Sungdong-ku, Seoul, 133-792, South Korea.
authors.forename: Jung Soon
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Pharmaceutical Division, Komipharm International Co., Ltd., Seoul, South Korea.|Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea.
authors.forename: Sujong
authors.initials: S
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, South Korea.
authors.forename: Hwa Jin
authors.initials: HJ
authors.lastname: Chung
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, South Korea.
authors.forename: Sang Kook
authors.initials: SK
authors.lastname: Lee
authors.affiliation: Division of Hematology, Department of Internal Medicine, Hanyang University College of Medicine, 17 Haengdang-dong, Sungdong-ku, Seoul, 133-792, South Korea.
authors.forename: Jun Ho
authors.initials: JH
authors.lastname: Yi
authors.affiliation: Division of Hematology, Department of Internal Medicine, Hanyang University College of Medicine, 17 Haengdang-dong, Sungdong-ku, Seoul, 133-792, South Korea.
authors.forename: Jieun
authors.initials: J
authors.lastname: Uhm
authors.affiliation: Division of Hematology, Department of Internal Medicine, Hanyang University College of Medicine, 17 Haengdang-dong, Sungdong-ku, Seoul, 133-792, South Korea.
authors.forename: Young Woong
authors.initials: YW
authors.lastname: Won
authors.affiliation: Division of Hematology, Department of Internal Medicine, Hanyang University College of Medicine, 17 Haengdang-dong, Sungdong-ku, Seoul, 133-792, South Korea.
authors.forename: Byeong Bae
authors.initials: BB
authors.lastname: Park
authors.affiliation: Division of Hematology, Department of Internal Medicine, Hanyang University College of Medicine, 17 Haengdang-dong, Sungdong-ku, Seoul, 133-792, South Korea.
authors.forename: Jung Hye
authors.initials: JH
authors.lastname: Choi
authors.affiliation: Division of Hematology, Department of Internal Medicine, Hanyang University College of Medicine, 17 Haengdang-dong, Sungdong-ku, Seoul, 133-792, South Korea. leeyy@hanyang.ac.kr.
authors.forename: Young Yiul
authors.initials: YY
authors.lastname: Lee
mesh_terms: D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D018053:Arsenites / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006801:Humans; D019169:Jurkat Cells; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D010087:Oxides / Q000494:pharmacology; D010865:Pilot Projects; D015398:Signal Transduction / Q000187:drug effects; D017670:Sodium Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D018053:Arsenites; D010087:Oxides; D017670:Sodium Compounds; C017947:sodium arsenite; D000077237:Arsenic Trioxide
keywords: Cell signal; KML001; Non-Hodgkin’s lymphoma; Sodium meta-arsenite; Telomere