비호지킨 림프종에서 Sodium Metaarsenite (KML001)의 체외 및 체내 반응

Abstract

Arsenic compounds have been used in traditional medicine for several centuries. Especially, arsenic trioxide (As2O3) has been shown to be effective in the treatment of acute promyelocytic leukemia (APL). KML001 (sodium metaarsenite/NaAsO2; Kominox) is an orally bio-available arsenic compound with potential anti-cancer activity. However, the effect of KML001 has not been well studied in lymphoid neoplasms.

The aim of this study was to evaluate the anti-proliferative effect of KML001 in non-Hodgkin’s lymphoma and to compare the efficacy with As2O3. In addition, the mechanisms underlying the anti-proliferative effects of KML001 were investigated.

KML001 inhibited the cellular proliferation in all tested lymphoma cell lines as well as JurkatR cells (doxorubicin-resistant Jurkat cells) in a dose-dependent manner with mean IC50 of 5 x 10-8M. While KML001 effectively inhibited cellular proliferation of Jurkat cells (IC50=5 x 10-8M) and JurkatR cells (IC50=1 x 10-8M), doxorubicin did not inhibit proliferation of JurkatR cells as expected. As2O3 was not as effective in lymphoma cell lines as KML001. KML001 induced G1 and G2/M arrest by regulating expressions and activities of various cell-cycle regulatory proteins. Apoptosis-modulating molecules such as BID and proforms of caspase-3 and caspase-9 were decreased in Jurkat cells and Bcl-2 and proforms of caspase-3 and caspase-9 were decreased in JurkatR cells by KML001 treatment. In addition, KML001 decreased the phosphorylated STAT5, GSK-3β and mTOR and increased phosphorylated PTEN. KML001 induced NF-κB (p65 and p50 subunits) down-regulation in a dose-dependent manner. In MAP kinase pathway, phosphorylated P38 and JNK were increased and phosphorylated ERK was decreased in KML001-treated Jurkat and JurkatR cells. Phosphorlated CHK1, CHK2 and γH2Ax of the DNA damage signal pathway were increased by KML001 treatment. Treatment with KML001 shortened the length of the telomere restriction fragment (TRF) in Jurkat and JurkatR cells. In vivo anti-lymphoma activity of KML001 was confirmed in a xenograft murine model with human lymphoma cells. Tumor burden was significantly reduced (P < 0.01) for 28 days. Especially, in-vivo anti-tumoral effect of 3.5 mg/kg KML001 was comparable to that of doxorubicin (2.5 mg/Kg, P < 0.05). In summary, KML001 demonstrated anti-tumoral effect via various mechanisms including cell cycle arrest, induction of apoptosis, and inhibition of JAK/STAT, PI3K and MAPK pathways. Especially, KML001 might target telomere with DNA damage. Furthermore, it is probable that KML001 may overcome the resistance of chemotherapeutic agents. Collectively, KML001 may be a candidate agent for the treatment of de novo, refractory and relapsed non-Hodgkin’s lymphoma.