ON 01910.Na Is Selectively Cytotoxic for Chronic Lymphocytic Leukemia Cells through a Dual Mechanism of Action Involving PI3K/AKT Inhibition and Induction of Oxidative Stress

Chapman, Colby M.; Sun, Xiameng; Roschewski, Mark; Aue, Georg; Farooqui, Mohamed; Stennett, Lawrence; Gibellini, Federica; Arthur, Diane C.; Pérez-Galán, Patricia; Wiestner, Adrian

doi:10.1158/1078-0432.ccr-11-2113

Cited by 72 publications

(82 citation statements)

References 51 publications

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“…57 Similarly, rigosertib, a PI3K␣/␤ inhibitor in advanced clinical testing for myelodysplastic syndromes, induced apoptosis in CLL cells cultured in contact with stromal cells. 58 Isoform selective targeting of the PI3K pathway appears to be an attractive option to prevent unwanted effects on normal cells. However, in transformed cells, the dominant role of a specific isoform may be lost and different isoforms can assume redundant functions.…”

Section: Pi3k Inhibitorsmentioning

confidence: 99%

Emerging role of kinase-targeted strategies in chronic lymphocytic leukemia

Wiestner

2012

Blood

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IntroductionOncogenic mutations in kinases have been identified in multiple cancers often leading to successful targeted therapy with kinase inhibitors. The paradigm in hematologic malignancies has been the discovery of the BCR-ABL fusion kinase in chronic myeloid leukemia and its successful targeting by tyrosine kinase inhibitors that changed the natural history of the disease. In contrast, possible disease-relevant mutations in kinases have been a rare finding in chronic lymphocytic leukemia (CLL). The most commonly mutated kinase in CLL is BRAF, with Ͻ 2% of patients affected. 1 However, kinase inhibitors that target signaling pathways that are essential for B-cell development, in particular, those targeting the B-cell receptor (BCR) have induced striking clinical responses. Here I briefly review these signaling pathways and discuss the ongoing clinical development of kinase inhibitors for the targeted therapy of CLL. Signaling pathways and their kinases in the pathogenesis of CLL Biology of CLLCLL is a malignancy of mature B cells involving blood, bone marrow, and lymphoid tissues. 2 CLL is the most common leukemia in Western countries and currently is most often diagnosed from an incidental blood count showing lymphocytosis. The median survival with early-stage disease is 10.7 years, but the clinical course is heterogeneous. 3 Two major CLL subtypes are distinguished by the presence or absence of somatic mutations in the immunoglobulin heavy chain variable region gene (IGHV), which encodes part of the antigen-binding domain of the BCR. Patients whose CLL cells express an unmutated IGHV gene (U-CLL) have a more rapidly progressive clinical course than patients whose CLL cells express a mutated IGHV gene (M-CLL). ZAP70, a nonreceptor tyrosine kinase essential for T-cell receptor signal transduction, is expressed in most cases of U-CLL and less frequently in M-CLL. ZAP70 expression correlates with more rapid disease progression in both subtypes defined by IGHV gene mutation status. 4The role of the microenvironment in CLL pathogenesis CLL cells in the blood are resting cells with a gene expression profile similar to memory B cells. 2 However, CLL cells in the lymph node and bone marrow show characteristics of activated B cells and demonstrate increased proliferation. 5 In the tissue sites, CLL proliferation is often highest in anatomic structures labeled as "proliferation centers" where CLL cells can interact with other cells, in particular T cells and stromal cells. 6 Thus, the biology of CLL cells in vivo depends on their anatomic location and is influenced by extrinsic signals from the tissue-microenvironment. In vitro, CLL cells undergo apoptosis unless appropriate microenvironmental factors are provided. This dependence of CLL cells on pathways that also promote normal B-cell development, expansion, and survival, [5][6][7][8][9] indicates that this tumor is "addicted to the host," constituting an example of a novel concept termed "non-oncogene addiction." 10 The term "microenvironment" collectively descri...

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Section: Pi3k Inhibitorsmentioning

confidence: 99%

Emerging role of kinase-targeted strategies in chronic lymphocytic leukemia

Wiestner

2012

Blood

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150

128

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“…SDF-1a/CXCL12-induced migration was evaluated in 24-well chemotaxis chambers containing 5 mm pore size inserts (Corning, Life Science) and performed as described (29). The migration index was calculated as the ratio between cells that migrated in response to SDF-1a divided by those that passively migrated without the chemokine.…”

Section: Migration Assaysmentioning

confidence: 99%

Disruption of Follicular Dendritic Cells–Follicular Lymphoma Cross-talk by the Pan-PI3K Inhibitor BKM120 (Buparlisib)

Matas-Céspedes¹,

Rodríguez²,

Kalko

et al. 2014

Clinical Cancer Research

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Purpose: To uncover the signaling pathways underlying follicular lymphoma-follicular dendritic cells (FL-FDC) cross-talk and its validation as new targets for therapy.Experimental Design: FL primary cells and cell lines were cocultured in the presence or absence of FDC. After 24 and 48 hours, RNA was isolated from FL cells and subjected to gene expression profiling (GEP) and data meta-analysis using DAVID and GSEA softwares. Blockade of PI3K pathway by the pan-PI3K inhibitor BKM120 (buparlisib; Novartis Pharmaceutical Corporation) and the effect of PI3K inhibition on FL-FDC cross-talk were analyzed by means of ELISA, RT-PCR, human umbilical vein endothelial cell tube formation, adhesion and migration assays, Western blot, and in vivo studies in mouse FL xenografts.Results: GEP of FL-FDC cocultures yields a marked modulation of FL transcriptome by FDC. Pathway assignment by DAVID and GSEA software uncovered an overrepresentation of genes related to angiogenesis, cell adhesion, migration, and serum-response factors. We demonstrate that the addition of the pan-PI3K inhibitor BKM120 to the cocultures was able to downregulate the expression and secretion of proangiogenic factors derived from FL-FDC cocultures, reducing in vitro and in vivo angiogenesis. Moreover, BKM120 efficiently counteracts FDC-mediated cell adhesion and impedes signaling and migration induced by the chemokine CXCL12. BKM120 inhibits both constitutive PI3K/AKT pathway and FDC-or CXCL12-induced PI3K/AKT pathway, hampers FDC survival signaling, and reduces cell proliferation of FL cells in vitro and in mouse xenografts.Conclusions: These data support the use of BKM120 in FL therapy to counteract microenvironmentrelated survival signaling in FL cells. Clin Cancer Res; 20(13); 3458-71. Ó2014 AACR.

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“…Moreover, whereas Cent-1 and rigosertib treatments lead to multipolarity, specific Plk1 inhibition with small molecules causes monopolarity (13). More recently, rigosertib was shown to inhibit the PI3K/AKT pathway (16,17). In our analysis, we did not observe significant changes in the phosphorylation status of AKT Ser473, a downstream target epitope of PI3K (40) upon Cent-1 or rigosertib treatment in insulinstimulated cells (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 48%

“…In this study, we described the identification and characterization of Cent-1, a novel LMW compound that possesses similar steric and electrostatic features and antimitotic phenotype as the template compound rigosertib, which is a multikinase inhibitor with claimed activity against PI3K and Plk1 pathways (11,16,17). The template compound has shown cytotoxic effects in human tumor cell lines and tumor growth suppression in xenograft models (11).…”

Section: Discussionmentioning

confidence: 99%

“…Because Plk1 is often overexpressed in cancer cells and its inhibition lowers tumor cells' viability (14), it is considered to be a promising drug target (15). In addition to targeting Plk1, rigosertib has been reported to show activity against phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways (11,16,17). However, the mechanism of action of the compound is not completely understood.…”

Section: Introductionmentioning

confidence: 99%

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Centmitor-1, a Novel Acridinyl-Acetohydrazide, Possesses Similar Molecular Interaction Field and Antimitotic Cellular Phenotype as Rigosertib, ON 01910.Na

Mäki-Jouppila

Laine

Rehnberg

et al. 2014

Molecular Cancer Therapeutics

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Mitosis is an attractive target for the development of new anticancer drugs. In a search for novel mitotic inhibitors, we virtually screened for low molecular weight compounds that would possess similar steric and electrostatic features, but different chemical structure than rigosertib (ON 01910.Na), a putative inhibitor of phosphoinositide 3-kinase (PI3K) and polo-like kinase 1 (Plk1) pathways. Highest scoring hit compounds were tested in cell-based assays for their ability to induce mitotic arrest. We identified a novel acridinyl-acetohydrazide, here named as Centmitor-1 (Cent-1), that possesses highly similar molecular interaction field as rigosertib. In cells, Cent-1 phenocopied the cellular effects of rigosertib and caused mitotic arrest characterized by chromosome alignment defects, multipolar spindles, centrosome fragmentation, and activated spindle assembly checkpoint. We compared the effects of Cent-1 and rigosertib on microtubules and found that both compounds modulated microtubule plus-ends and reduced microtubule dynamics. Also, mitotic spindle forces were affected by the compounds as tension across sister kinetochores was reduced in mitotic cells. Our results showed that both Cent-1 and rigosertib target processes that occur during mitosis as they had immediate antimitotic effects when added to cells during mitosis. Analysis of Plk1 activity in cells using a Förster resonance energy transfer (FRET)-based assay indicated that neither compound affected the activity of the kinase. Taken together, these findings suggest that Cent-1 and rigosertib elicit their antimitotic effects by targeting mitotic processes without impairment of Plk1 kinase activity.

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ON 01910.Na Is Selectively Cytotoxic for Chronic Lymphocytic Leukemia Cells through a Dual Mechanism of Action Involving PI3K/AKT Inhibition and Induction of Oxidative Stress

Cited by 72 publications

References 51 publications

Emerging role of kinase-targeted strategies in chronic lymphocytic leukemia

Emerging role of kinase-targeted strategies in chronic lymphocytic leukemia

Disruption of Follicular Dendritic Cells–Follicular Lymphoma Cross-talk by the Pan-PI3K Inhibitor BKM120 (Buparlisib)

Centmitor-1, a Novel Acridinyl-Acetohydrazide, Possesses Similar Molecular Interaction Field and Antimitotic Cellular Phenotype as Rigosertib, ON 01910.Na

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