AT514, a cyclic depsipeptide from Serratia marcescens, induces apoptosis of B-chronic lymphocytic leukemia cells: interference with the Akt/NF-κB survival pathway

Escobar-Díaz, Elizabeth; López-Martín, E M; Cerro, Mercedes Hernández del; Puig‐Kröger, Amaya; Soto‐Cerrato, Vanessa; Montaner, Beatriz; Giralt, Ernest; García-Marco, José A.; Pérez-Tomás, Ricardo; García-Pardo, Ángeles

doi:10.1038/sj.leu.2403679

Cited by 37 publications

(20 citation statements)

References 37 publications

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“…The PI3K/Akt signaling pathway is constitutively activated in many B-CLL cases, as we also find in our study, and contributes to the typical B-CLL cell antiapoptotic phenotype (23,24). In this report we show for the first time that suboptimal concentrations of ATO (2 μmol/L) specifically cooperated with pharmacologic inhibitors of the PI3K survival pathway and enhanced B-CLL cell apoptosis.…”

Section: Discussionsupporting

confidence: 49%

“…ATO cooperates with PI3K/Akt inhibitors to enhance B-CLL cell apoptosis and inhibits Akt activation by upregulating PTEN The PI3K/Akt and protein kinase C (PKC) signaling pathways are constitutively activated in many B-CLL cases and contribute to their resistance to apoptosis (23,24). We studied whether the combination of ATO and PI3K/ Akt or PKC inhibitors enhanced the apoptotic effect of either agent alone.…”

Section: Ato Induces Apoptosis Of B-cll Cells But Not Of Normal Pblmentioning

confidence: 99%

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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 c-jun-NH2 Terminal Kinase Activation and PTEN Upregulation

Redondo-Muñóz

Escobar-Díaz

Cerro

et al. 2010

Clinical Cancer Research

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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 combination 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 phosphoinositide 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-NH 2 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 mitochondrial 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.

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Section: Discussionsupporting

confidence: 49%

Section: Ato Induces Apoptosis Of B-cll Cells But Not Of Normal Pblmentioning

confidence: 99%

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

Redondo-Muñóz

Escobar-Díaz

Cerro

et al. 2010

Clinical Cancer Research

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“…In this context, it is noteworthy that several other NF-B inhibitors have also shown promise in preclinical evaluation in primary CLL cells. 23,24, [43][44][45][46] The development of drug resistance is a major clinical problem in CLL. [47][48][49][50][51] Therefore, it is important to note that sensitivity to LC-1 was For personal use only.…”

Section: Discussionmentioning

confidence: 99%

The NF-κB subunit Rel A is associated with in vitro survival and clinical disease progression in chronic lymphocytic leukemia and represents a promising therapeutic target

Hewamana

Alghazal²,

Lin³

et al. 2008

Blood

145

132

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In this study, we characterized nuclear factor B (NF- B IntroductionB-cell chronic lymphocytic leukemia (CLL) is a malignancy characterized by the accumulation of CD5, CD19, and CD23 positive lymphocytes. Diagnosis is aided by the CLL immunophenotyping score which includes assessment of CD5 and CD23, FMC7, CD79b, and surface IgM. 1 Although CLL is the commonest leukemia in the Western world, it manifests a very heterogeneous clinical course, with some patients having normal age-adjusted survival, whereas the median survival for those patients with advanced stage disease is only 3 years. 2 The factors that contribute to the pathogenesis and progression of this disease are poorly understood, but decreased susceptibility to apoptosis 3 and dysregulated proliferation have been implicated. 4 Clinical studies have shown that high ZAP-70 expression, high CD38 expression, unmutated V H genes, and cytogenetic abnormalities (especially deletions of 11q and 17p) are all associated with a poor prognosis. [5][6][7][8][9] Nuclear factor B (NF-B) is a collective name for a group of inducible homodimeric and heterodimeric transcription factors made up of members of the Rel family of DNA-binding proteins. In humans, this family is composed of c-Rel, Rel B, p50, p52, and Rel A (p65) which, when bound in the cytoplasm to inhibitor of NF-B (IB) proteins, are inactive. 10,11 Various factors, including ligation of CD40 or the B-cell receptor (BCR), result in proteosomal degradation of IB releasing NF-B, which then translocates to the nucleus. 10,11 Once in the nucleus, NF-B can enhance survival by inducing apoptosis inhibitory proteins, including inhibitor of apoptosis proteins (IAPs), Fas-associated death domain (FADD)-like interleukin (IL)-1␤-converting enzyme (FLICE), and FADD-like IL-1␤-converting enzyme-inhibitory protein (FLIP). 12-14 CLL cells have been reported to exhibit high constitutive NF-B activation compared with normal B lymphocytes. [15][16][17] Although the exact factors responsible for the constitutive expression of NF-B are not fully resolved, many factors, including Akt activation, BCR signaling, CD40 ligation, IL-4, and B-cell activating factor (BAFF), have been shown to increase NF-B activity and enhance CLL cell survival, with members of the Bcl-2 family being principal transcriptional targets. [18][19][20][21][22] Several recent studies have demonstrated the proof of concept of the effectiveness of targeting NF-B in hematologic malignancies, including CLL 23,24 and acute myeloid leukemia. 25,26 In this study, we first set out to determine the range of constitutive DNA binding of NF-B within our patient cohort and to characterize the specific subunits of NF-B in these primary CLL cells. We then went on to investigate the ability of freshly isolated CLL cells to induce NF-B expression in response to BCR Submitted November 20, 2007; accepted January 25, 2008. Prepublished online as Blood First Edition paper, January 28, 2008; DOI 10.1182 DOI 10. /blood-2007 An Inside Blood analysis of this article appears at ...

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“…44 This accumulation is probably caused by reduced apoptosis rather than increased proliferation. 44 One study demonstrated that unstimulated B-CLL cells obtained from patient samples exhibited higher levels of NF-kB activity than human B cells from healthy donors. 45 As dominant NFkB component's the transcriptionally active subunits p50, p65, and c-Rel were identified in this report.…”

Section: B-cllmentioning

confidence: 99%

Targeting NF-κB in hematologic malignancies

et al. 2006

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The transcription factor nuclear factor kappa B (NF-jB) can intervene in oncogenesis by virtue of its capacity to regulate the expression of a plethora of genes that modulate apoptosis, and cell survival as well as proliferation, inflammation, tumor metastasis and angiogenesis. Different reports demonstrate the intrinsic activation of NF-jB in lymphoid and myeloid malignancies, including preneoplastic conditions such as myelodysplastic syndromes, underscoring its implication in malignant transformation. Targeting intrinsic NF-jB activation, as well as its upstream and downstream regulators, may hence constitute an additional approach to the oncologist's armamentarium. Several small inhibitors of the NF-jB-activatory kinase IjB kinase, of the proteaseome, or of the DNA binding of NF-jB subunits are under intensive investigation. Currently used cytotoxic agents can induce NF-jB activation as an unwarranted side effect, which confers apoptosis suppression and hence resistance to these drugs. Thus, NF-jB inhibitory molecules may be clinically useful, either as single therapeutic agents or in combination with classical chemotherapeutic agents, for the treatment of hematological malignancies.

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AT514, a cyclic depsipeptide from Serratia marcescens, induces apoptosis of B-chronic lymphocytic leukemia cells: interference with the Akt/NF-κB survival pathway

Cited by 37 publications

References 37 publications

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

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

The NF-κB subunit Rel A is associated with in vitro survival and clinical disease progression in chronic lymphocytic leukemia and represents a promising therapeutic target

Targeting NF-κB in hematologic malignancies

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