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Induction of B-Chronic Lymphocytic Leukemia Cell Apoptosis by Arsenic Trioxide Involves Suppression of the Phosphoinositide 3-Kinase/Akt Survival Pathway Via

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Induction of B-Chronic Lymphocytic Leukemia Cell Apoptosis by Arsenic Trioxide Involves Suppression of the Phosphoinositide 3-Kinase/Akt Survival Pathway Via Published OnlineFirst June 9, 2010; DOI: 10.1158/1078-0432.CCR-10-0072 Published OnlineFirst on August 24, 2010 as 10.1158/1078-0432.CCR-10-0072 Cancer Therapy: Preclinical Clinical Cancer See commentary p. 4311 Research Induction of B-Chronic Lymphocytic Leukemia Cell Apoptosis by Arsenic Trioxide Involves Suppression of the Phosphoinositide 3-Kinase/Akt Survival Pathway via c-jun-NH2 Terminal Kinase Activation and PTEN Upregulation Javier Redondo-Muñoz1, Elizabeth Escobar-Díaz1, Mercedes Hernández del Cerro1, Atanasio Pandiella3, María José Terol4, José A. García-Marco2, and Angeles García-Pardo1 Abstract Purpose: Arsenic trioxide (ATO) induces B-cell chronic lymphocytic leukemia (B-CLL) cell apoptosis in vitro. We sought to study the mechanism involved in this effect and whether ATO is suitable for com- bination therapies with protein kinase inhibitors. Experimental Design: B-CLL cells were isolated from the peripheral blood of 28 patients. Cell viability studies with ATO alone or in combination with kinase inhibitors were done by flow cytometry, Western blotting, and immunofluorescence analyses. Results: After 48 hours, 3 μmol/L ATO induced apoptosis (average 75%) in all B-CLL samples studied and with minimal effect on normal peripheral blood lymphocytes. Apoptosis entailed Akt and NF-κB inactivation, XIAP downregulation, and PTEN upregulation, thus implying inhibition of the phosphoi- nositide 3-kinase (PI3K) survival pathway. Indeed, the combination of ATO and PI3K inhibitors increased the apoptotic effect of either agent alone. ATO also induced c-jun-NH2 terminal kinase (JNK) activation, and this was crucial and required for subsequent apoptotic events, as inhibiting JNK activity by either gene silencing or specific inhibitors prevented Akt and NF-κB inactivation, caspase activation, and mito- chondrial damage. Moreover, JNK activation was the earliest response to ATO, preceding and determining reactive oxygen species production. Conclusions: We identified the mechanism involved in ATO action on B-CLL cells and show that the combination of low doses of ATO and PI3K inhibitors efficiently induces B-CLL cell death. ATO may therefore constitute an efficient treatment for B-CLL, particularly in combined therapies. Clin Cancer Res; 16(17); 4382–91. ©2010 AACR. B-cell chronic lymphocytic leukemia (B-CLL) is charac- IgVH unmutated status) seem to be associated with poor terized by the accumulation of malignant CD5+ B lympho- response to therapy and worse prognosis (1, 2). Most cur- cytes in the peripheral blood, and their progressive rent treatments for B-CLL consist in the administration of infiltration of lymphoid tissues (1, 2). The course of the the purine analogue fludarabine, either alone or in combi- disease is very heterogeneous, and several molecular mar- nation with other therapeutic drugs (3, 4). Although many kers (high CD38 or/and ZAP-70 expression, del17p13, patients respond well to these protocols and complete re- mission can be attained, patients eventually relapse and may die from the disease. It is therefore crucial to continue Authors' Affiliations: 1Departamento de Medicina Celular y Molecular, searching for new compounds that could be useful in the Centro de Investigaciones Biológicas, Consejo Superior de treatment of this type of leukemia, especially in the ad- Investigaciones Científicas and 2Servicio de Hematología, Hospital Universitario Puerta de Hierro, Madrid, Spain; 3Centro de Investigación vanced setting. del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain; and Arsenic trioxide (ATO) has been used in traditional 4Departamento de Hematología y Oncología Médica, Hospital Clínico, Valencia, Spain Chinese medicine and is currently successfully employed for the treatment of acute promyelocytic leukemia (APL; Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). refs. 5–8). ATO is also being trialed for other hematologic J. Redondo-Muñoz and E. Escobar-Díaz contributed equally to this work. malignancies, including chronic myeloid leukemia, mye- lodysplastic syndrome, and non-M3 acute myelocytic leu- Corresponding Author: Angeles García-Pardo, Centro de Investigaciones Biológicas, Ramiro de Maeztu 9, 28040 Madrid, Spain. Phone: 34-91-837- kemia and multiple myeloma, either as monotherapy or 3112; Fax: 34-91-536-0432; E-mail: [email protected]. combined therapy (7, 9). The cytotoxic effect of ATO on doi: 10.1158/1078-0432.CCR-10-0072 these systems involves complex mechanisms that are not ©2010 American Association for Cancer Research. fully understood. In many cases, induction of apoptosis 4382 Clin Cancer Res; 16(17) September 1, 2010 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2010 American Association for Cancer Research. Published OnlineFirst June 9, 2010; DOI: 10.1158/1078-0432.CCR-10-0072 PTEN and JNK in ATO-Induced B-CLL Cell Apoptosis was >95% CD19+, >70% CD5+, considered suitable for Translational Relevance subsequent studies. Purified B-CLL cells were either used immediately or frozen and stored in liquid nitrogen. B-cell chronic lymphocytic leukemia (B-CLL) re- Peripheral blood lymphocytes (PBL; T plus B lympho- mains an incurable disease, making it crucial to con- cytes) from five adult healthy donors were obtained from tinue searching for novel therapies. Arsenic trioxide buffy coat preparations routinely used for monocytic cell (ATO) is an efficient treatment for acute promyelocytic purification. After Ficoll-Hypaque centrifugation, mono- leukemia, and it is being trialed for other hematologic cytic cells were removed using anti-CD14-conjugated malignancies. To explore the potential clinical use of microbeads and MACS separation columns (Miltenyi ATO in B-CLL we studied the mechanism by which Biotec). B-CLL and control cells were cultured at 1.5 × ATO induces apoptosis in B-CLL cells. We report that 106/mL in RPMI/10% fetal bovine serum, 100 μg/mL JNK and PTEN are crucial molecules and inhibit phos- gentamicin and penicillin, and 100 U/mL streptomycin phoinositide 3-kinase (PI3K) survival signaling in (Invitrogen Ltd.). response to ATO. Accordingly, PI3K inhibitors effi- Approval was obtained from the Consejo Superior de ciently enhanced the apoptotic effect of ATO. These ef- Investigaciones Científicas Bioethics Review Board for fects were observed at low, nontoxic ATO doses and in these studies. all cases studied. Our results strongly suggest that ATO alone or combined with PI3K inhibitors may be con- RNA interference experiments sidered an alternative therapy for B-CLL. The small interfering RNA (siRNA) sequence targeting JNK: sense 5′-CAAAGAUCCCUGACAAGCAdTT-3′ (s11153), and the control siRNA sequence: sense 5′-AUU- ′ by ATO involves the release of reactive oxygen species GUAUGCGAUCGCAGACdTT-3 , were custom-made (ROS), and experimental reduction of glutathione peroxi- by Ambion. For transfection of B-CLL cells, siRNAs μ dase increases the sensitivity to ATO (10, 11). Blocking (500 nmol/L final concentration) in 100 LRPMIwere the extracellular signal-regulated kinase (ERK)/ERK, phos- incubated at room temperature for 10 minutes with – 4.5 μL HiPerfect transfection reagent (Qiagen). The mixture phoinositide 3-kinase (PI3K)/Akt, or p38 mitogen-activated 6 protein kinase signaling pathways has also been shown to was added dropwise to 2 × 10 cells in RPMI/10% FCS, and enhance the apoptotic effect of ATO on APL, myeloma, transfected cells were used after 24 hours. The efficiency of and T-leukemia cells (10, 12–15). Additionally, ATO- gene silencing was analyzed by Western blotting. induced apoptosis of myeloma and APL cells involves the activation of c-jun-NH-kinase (JNK; refs. 16, 17). Analysis of apoptosis and mitochondrial membrane Δψ Very few studies have addressed the effect of ATO on potential ( m) 5 μ B-CLL cells. In analyses of a small number of B-CLL sam- B-CLL cells (1.5 × 10 ) in 100 L RPMI/10% fetal ples (18) or long exposure times (19), ATO was shown bovine serum were placed in 96-well plates and treated with various concentrations of ATO or vehicle (PBS). After to induce apoptosis of B-CLL cells, concomitant with 6 downregulation of Bcl-2. ATO also induced ROS genera- 24 to 48 hours cells were suspended (10 /mL) in 1× bind- μ tion and significantly enhanced the cytotoxic activity of ing buffer (Bender Medsystems), containing either 3 L μ 2-methoxyestradiol and ascorbic acid on B-CLL samples FITC-Annexin V and 50 g propidium iodide (PI), or (20, 21). It was recently reported that ATO preferentially PI alone. After 10 minutes, cells were analyzed by flow induced apoptosis in B-CLL cases with unfavorable prog- cytometry on a Coulter Epics XL. For combined treat- nosis (22). These previous studies strongly suggest that ments, B-CLL cells were incubated for 30 minutes with μ ATO, alone or in combination with other treatments, either SP600125 (10 mol/L), SB203580, BisI, UO126, μ could be an efficient therapeutic agent for B-CLL. The Tricirbine/API-2, LY294002 (all at 5 mol/L), Z-VAD- μ mechanism by which ATO induces B-CLL cell apoptosis FMK, or Z-IETD-FMK (both at 50 mol/L) prior to the ad- μ Δψ has not been established, and we have addressed this in dition of 2 mol/L ATO. For m measurements, B-CLL the present report. cells were incubated for 24 hours with or without 3 μmol/L ATO and treated for 20 minutes with 20 nmol/L DiOC6 (Cabiochem) at room temperature in the dark. Cells Materials and Methods were washed, resuspended in PBS, and analyzed by flow cytometry. Patients, B-CLL cell purification, and normal peripheral blood lymphocytes Measurement of intracellular ROS accumulation Following informed consent, B-CLL cells were purified B-CLL cells (5 × 105) were treated with or without from the peripheral blood of 28 patients (Table 1) by SP600125 (2-10 μmol/L), NAC (10 mmol/L), or MnTBAP Ficoll-Hypaque (Nycomed) centrifugation and anti-CD3- (50 μmol/L) for 30 minutes and cultured in the presence conjugated Dynabeads (Dynal Biotech ASA). Myeloid cells or absence of 3 μmol/L ATO.
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