The pharmacological NFκB inhibitors BAY117082 and MG132 induce cell arrest and apoptosis in leukemia cells through ROS-mitochondria pathway activation

Zanotto-Filho, Alfeu; Cañedo, Andrés Delgado; Schröder, Rafael; Becker, Matheus William; Klamt, Fábio; Moreira, José Cláudio Fonseca

doi:10.1016/j.canlet.2009.06.038

Cited by 59 publications

(36 citation statements)

References 37 publications

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“…This suggests that induction of ROS and subsequently Nrf2 nuclear accumulation in monocytes are independent of NF-kB activation. Moreover, blocking NF-kB activity alone or in combination with TNF has been shown to increase the levels of ROS, which can induce apoptosis (21,30,31). In this study, no apoptosis was observed in human monocytes by the treatment of NF-kB inhibition.…”

Section: Discussionmentioning

confidence: 50%

TNF Mediates the Sustained Activation of Nrf2 in Human Monocytes

Rushworth

Shah

MacEwan

2011

The Journal of Immunology

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Modulation of monocyte function is a critical factor in the resolution of inflammatory responses. This role is mediated mainly by the production of TNF-a. Investigations of the actions of TNF have mostly focused on acute activation of other cell types such as fibroblasts and endothelial cells. Less is known about the effects of TNF on monocytes themselves, and little is known about the regulation of cell responses to TNF beyond the activation of NF-?B. In this study, we investigated the regulation of NF-E2–related factor 2 (Nrf2) cyctoprotective responses to TNF in human monocytes. We found that in monocytes TNF induces sustained Nrf2 activation and Nrf2 cytoprotective gene induction in a TNFR1-dependent manner. Under TNF activation, monocytes increased their expression of Nrf2-dependent genes, including NAD(P)H:quinone oxidoreductase 1 and glutamyl cysteine ligase modulatory, but not heme oxygenase-1. We also showed that autocrine TNF secretion was responsible for this sustained Nrf2 response and that Nrf2 activation by TNF was mediated by the generation of reactive oxygen species. Moreover, we showed that Nrf2-mediated gene induction can modulate TNF-induced NF-?B activation. These results show for the first time, to our knowledge, that TNF modulates prolonged Nrf2-induced gene expression, which in turn regulates TNF-induced inflammatory responses

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Section: Discussionmentioning

confidence: 50%

TNF Mediates the Sustained Activation of Nrf2 in Human Monocytes

Rushworth

Shah

MacEwan

2011

The Journal of Immunology

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“…Likewise, abrogating TLR2/PI3K/Akt-dependent mechanisms by inhibition with LY294002 failed to protect cardiomyocytes against doxorubicin-induced cardiomyopathy [83] and brain cells against ischemic injury [84]. Our results demonstrate that NF-κB or PI3K inhibition showed a dose-dependent cytotoxic effect on ALL cells, consistent with reports that both pathways contribute to the survival advantage of leukemic blasts [85,86]. Based on our results, it appears that NF-κB and PI3K suppress proapoptotic signals generated by Pam 2 CSK 4 through simultaneous induction of prosurvival pathways, and still have the capacity to dampen the full extent of Pam 3 CSK 4 -mediated apoptosis in ALL cells, as their inhibition at concentrations that do not induce relevant cytotoxicity on their own augmented Pam 3 CSK 4 -mediated cell death and transformed Pam 2 CSK 4 into a cell-death inducing agent.…”

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confidence: 88%

Heterodimer‐specific TLR2 stimulation results in divergent functional outcomes in B‐cell precursor acute lymphoblastic leukemia

et al. 2015

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Reports of spontaneous acute lymphoblastic leukemia (ALL) remissions following severe bacterial infections suggest that bacterial components may trigger elimination of ALL. To date, TLR2, which recognizes a broad range of bacterial pathogens through TLR1 or TLR6 heterodimerization, has not been fully evaluated for direct effects on ALL. Studies investigating TLR2 signaling in other tumor cell types utilizing single ligands have yielded contradictory results, and comparative, heterodimer-specific analyses of TLR2 stimulation are lacking. In this study, we report that two well-characterized heterodimer-specific TLR2 ligands, Pam 3 CSK 4 (TLR2/1), and Pam 2 CSK 4 (TLR2/6), induce ALL cell lines and primary ALL samples to upregulate CD40 expression. However, only Pam 3 CSK 4 triggers Caspase-8-mediated apoptosis and sensitizes cells to vincristine-mediated cytotoxicity. Consistent with this result, stimulation of ALL cells through TLR2/1 or TLR2/6 activates Mal, p38 and the NF-κB and PI3K signaling pathways with divergent kinetics that may underlie their distinct downstream effects. Our results reveal a novel branching in downstream responses to heterodimer-specific TLR2 stimulation in ALL cells and emphasize the need for comparative studies to determine differential biological effects observed in specific tumor cells. Based on our results, TLR2/1 ligand Pam 3 CSK 4 possesses potential for generating anti-ALL activity through its direct effects on leukemic blasts.Keywords: CD40 r Caspase-8-mediated apoptotic cell death r Heterodimer-specific TLR2 stimulation r Pediatric acute lymphoblastic leukemia r Signaling kinetics Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionIt is now widely accepted that tumor remissions induced by the proinflammatory activity of Coley's toxin, which contains various bacterial components, is mediated by the engagement of TollCorrespondence: Dr. Kirk R. Schultz e-mail: kschultz@mail.ubc.ca like receptors (TLRs) on immune cells [1][2][3][4][5]. TLRs are a family of germline-encoded pattern recognition receptors that induce innate and adaptive immune responses after binding pathogenand damage-associated molecular patterns [6][7][8][9][10]. In recent years, many studies have demonstrated that purified TLR ligands exert * These authors contributed equally to this work as senior authors.www.eji-journal.eu Eur. J. Immunol. 2015. 45: 1980-1990 Immunomodulation 1981 potent anti-cancer effects against various types of established tumors in both mice and humans [2,5]. However, while some TLR ligands are currently in clinical trials [11,12], their promising preclinical efficacy as anti-cancer agents has not been consistently observed in the clinic [12]. A greater understanding of the cellular and molecular processes that mediate the beneficial and detrimental outcomes of TLR signaling is needed in order to optimize the translation of this approach. Spontaneous remissions of acute lymphoblastic leukemia (ALL) associated with se...

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“…NFκB is bound to the inhibitory protein IκB, which retains NFêB within the cytosol thus preventing its transcriptional activity. Bay 11-7082 inhibits IKK and parthenolide inhibits NFκB, effects considered to contribute to their negative effect on cell survival [7]. Considering the restricted specifity of Bay 11-7082 and parthenolide [8,9,[44][45][46], and the lack of an inhibitory effect of Bay 11-7082 on the phosphorylation status of IκB-α, the pharmacological evidence in favour of a functional role for NFκB in the regulation of erythrocyte survival is limited.…”

Section: Discussionmentioning

confidence: 99%

“…IκB 46 phosphorylation by IκB kinase (IKK) prepares IκB for ubiquitination and subsequent degradation. Pharmacological inhibition of IKK by Bay 11-7082 or of NFκB by parthenolide trigger apoptosis [4][5][6][7]. Beyond that, the substances may in addition compromize cell function and survival by interference with NFκB-independent mechanisms, such as caspase 1 [8,9].…”

Section: Introductionmentioning

confidence: 99%

The NFĸB Pathway Inhibitors Bay 11-7082 and Parthenolide Induce Programmed Cell Death in Anucleated Erythrocytes

Ghashghaeinia

Toulany

Saki

et al. 2011

Cell Physiol Biochem

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The preclinical compounds Bay 11-7082 and parthenolide trigger apoptosis, an effect contributing to their antiinflammatory action. The substances interfere with the activation and nuclear translocation of nuclear factor NFĸB, by inhibiting NFĸB directly (parthenolide) or by interfering with the inactivation of the NFĸB inhibitory protein IĸB-α (Bay 11-7082). Beyond that, the substances may be effective in part by nongenomic effects. Similar to apoptosis of nucleated cells, erythrocytes may undergo apoptosis-like cell death (eryptosis) characterized by cell membrane scrambling with phosphatidylserine exposure, and cell shrinkage. Thus, erythrocytes allow the study of nongenomic mechanisms contributing to suicidal cell death, e.g. Ca²⁺ leakage or glutathione depletion. The present study utilized Western blotting to search for NFĸB and IĸB-α expression in erythrocytes, FACS analysis to determine cytosolic Ca²⁺ (Fluo3 fluorescence), phosphatidylserine exposure (annexin V binding), and cell volume (forward scatter), as well as an enzymatic method to determine glutathione levels. As a result, both NFĸB and IĸB-α are expressed in erythrocytes. Targeting the NFĸB pathway by Bay 11-7082 (IC₅₀ ≈ 10 µM) and parthenolide (IC₅₀ ≈ 30 µM) triggered suicidal erythrocyte death as shown by annexin V binding and decrease of forward scatter. Bay 11-7082 treatment further increased intracellular Ca²⁺ and led to depletion of reduced glutathione. The effects of Bay 11-7082 and parthenolide on annexin V binding could be fully reversed by the antioxidant N-acetylcysteine. In conclusion, the pharmacological inhibitors of NFĸB, Bay 11-7082 and parthenolide, interfere with the survival of erythrocytes involving mechanisms other than disruption of NFĸB-dependent gene expression.

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The pharmacological NFκB inhibitors BAY117082 and MG132 induce cell arrest and apoptosis in leukemia cells through ROS-mitochondria pathway activation

Cited by 59 publications

References 37 publications

TNF Mediates the Sustained Activation of Nrf2 in Human Monocytes

TNF Mediates the Sustained Activation of Nrf2 in Human Monocytes

Heterodimer‐specific TLR2 stimulation results in divergent functional outcomes in B‐cell precursor acute lymphoblastic leukemia

The NFĸB Pathway Inhibitors Bay 11-7082 and Parthenolide Induce Programmed Cell Death in Anucleated Erythrocytes

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