Arsenic Trioxide Induces Apoptosis in Chronic Myelogenous Leukemia K562 Cells:Possible Involvement of p38 MAP Kinase

Abstract

Arsenic trioxide (As 2 O 3 ) was recently demonstrated to be an effective inducer of apoptosis in patients with relapsed acute promyelocytic leukemia (APL) as well as in patients with APL in whom all-trans-retinoic acid and conventional chemotherapy failed. Chronic myelogenous leukemia cells are highly resistant to chemotherapeutic drugs. To determine if As 2 O 3 might be useful for the treatment of chronic myelogenous leukemia, we examined the ability of As 2 O 3 to induce apoptosis in K562 cells. In vitro cytotoxicity of As 2 O 3 was evaluated in K562 cells by a MTT assay; the IC 50 value for As 2 O 3 was determined to be 10 µM. When analyzed by agarose gel electrophoresis, the DNA fragments became evident after incubation of the cells with 20 µM As 2 O 3 for 24 h. We also found morphological changes and chromatin condensation of the cells undergoing apoptosis. Activation of caspase-3 was observed 6 h after treatment with 20 µM As 2 O 3 by a Western blot analysis. Next, we examined the MAP kinasesignaling pathway of As 2 O 3 -induced apoptosis in K562 cells. As 2 O 3 at 10 µM strongly induced the activation of p38 and JNK 1/2, while ERK 1/2 was inhibited. In addition, pretreatment of SB203580, a specific inhibitor of p38, inhibited As 2 O 3 induced apoptotic cell death. These results suggest that As 2 O 3 is able to induce the apoptotic activity in K562 cells, and its apoptotic mechanism may be associated with the activation of p38.

Arsenic trioxide and proteasome inhibitor bortezomib synergistically induce apoptosis in leukemic cells: the role of protein kinase Cδ

“…45 However, ATO-induced apoptosis in HepG 2 cells was shown to be independent of MAP kinase signaling pathways. 46 Consistent to Shim's report, 26 here we showed that ATO at 1 mM slightly activated p38 but not JNK, while bortezomib activated both JNK and p38. More significantly, both JNK and p38 were greatly activated by combined treatment of bortezomib and ATO, suggesting possible contribution of these two kinases in their synergistic effect in term of apoptosis induction.…”

“…[35][36][37] ATO at 10 mM was also reported to induce the activation of p38 and JNK with the inhibition extracellular signal-regulated kinase (ERK). 26 Consequently, we tested potential effects of bortezomib or/and ATO on these two kinases in K562 cells. As shown in Figure 5, bortezomib (32 nM) induced JNK and p38 activations, while ATO (1 mM) only slightly activated p38, as evidenced by their phosphorylated levels.…”

“…[18][19][20][21][22] Based on this exciting discovery, some reports showed that ATO or its combination with other chemotherapeutic drugs could also induce apoptosis and/or growth arrest in Bcr-Abl þ cells. [23][24][25] However, higher concentrations of ATO, with 10mM of the IC 50 value, 26 were used in these works. In this work, we investigated possible synergy between bortezomib and clinically relevant ATO in Bcr-Abl þ leukemia K562 cell line and other leukemic cells in general.…”

The role of Akt on Arsenic trioxide suppression of 3T3-L1 preadipocyte differentiation

“…events for apoptosis [18]. It should be noted that arsenic trioxide activate a number of signaling pathways, such as MAPK, ERK and JNK or suppress certain signaling pathways [19,20]. The molecular details of the network of different signaling molecules to regulate cell differentiation need to be further investigation.…”

Coordination of intrinsic, extrinsic, and endoplasmic reticulum-mediated apoptosis by imatinib mesylate combined with arsenic trioxide in chronic myeloid leukemia

“…30 At subtoxic or clinically achievable concentrations (0.5-2 M), however, the effectiveness of ATO in apoptotic induction appears to be significantly reduced, resulting in prolonged proapoptotic periods (eg, 7-10 days). 31 Accordingly, transcriptome changes depicted by CPP-SOM of the ATO-treated series may mainly reflect proapoptotic activities induced by a low dose of ATO.…”