Brefeldin A Induces Apoptosis and Cell Cycle Blockade in Glioblastoma Cell Lines

Pommepuy, Isabelle; Terro, Faraj; Petit, Barbara; Trimoreau, Frank; Bellet, Virginie; Robert, Sandrine; Hugon, Jacques; Labrousse, François; Yardin, Catherine

doi:10.1159/000070307

Cited by 20 publications

(12 citation statements)

References 31 publications

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“…The ability of BFA to induce apoptosis independent of p53 status has also been noted in other types of malignant cells. 74,75 In contrast, Figure 5. Brefeldin A inhibits VEGF secretion.…”

Section: Discussionmentioning

confidence: 89%

Targeting endoplasmic reticulum protein transport: a novel strategy to kill malignant B cells and overcome fludarabine resistance in CLL

Carew

Nawrocki

Krupnik

et al. 2006

Blood

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Previous studies showed that chronic lymphocytic leukemia (CLL) cells exhibit certain mitochondrial abnormalities including mtDNA mutations, increased superoxide generation, and aberrant mitochondrial biogenesis, which are associated with impaired apoptosis and reduced sensitivity to fludarabine. Here we report that CLL cells and multiple myeloma cells are highly sensitive to brefeldin A, an inhibitor of endoplasmic reticulum (ER) to Golgi protein transport currently being developed as a novel anticancer agent in a prodrug formulation. Of importance, brefeldin A effectively induced apoptosis in fludarabine-refractory CLL cells. Disruption of protein trafficking by brefeldin A caused the sequestration of the prosurvival factors APRIL and VEGF in the ER, leading to abnormal ER swelling and a decrease in VEGF secretion. Such ER stress and blockage of secretory protein traffic eventually resulted in Golgi collapse, activation of caspases, and cell death. Notably, the cellular sensitivity to this compound appeared to be independent of p53 status. Taken together, these findings suggest that malignant B cells may be highly dependent on ER-Golgi protein transport and that targeting this process may be a promising therapeutic strategy for B-cell malignancies, especially for those that respond poorly to conventional treatments. IntroductionChronic lymphocytic leukemia (CLL) is a common adult leukemia with unique characteristics in that the disease progression involves the persistent accumulation of apparently quiescent B cells, primarily due to defects in apoptosis rather than increased cell proliferation. 1 The apoptotic resistance of CLL cells has been attributed, in part, to high expression of antiapoptotic proteins such as Bcl-2, Bcl-X L , and Mcl-1. [2][3][4][5][6][7][8] Our previous work demonstrated that CLL cells contain multiple mitochondrial defects including mtDNA mutations, aberrant mitochondrial biogenesis, and increased generation of the oxygen radical superoxide, which is predominantly produced in the mitochondria. These abnormalities are associated with alterations in sensitivity to anticancer agents, suggesting that they may compromise the execution of the mitochondrial apoptotic machinery. [9][10][11] Fludarabine and alkylating agents have significantly improved clinical outcomes of CLL treatment. However, there are currently limited effective therapeutic options for patients that are refractory to these agents. 1,12,13 Thus, identification and evaluation of novel agents for the treatment of refractory CLL are important and challenging tasks. While investigating the mechanistic basis of aberrant mitochondrial biogenesis activity in primary CLL cells, we observed that in addition to increased mitochondrial content, CLL cells also appear to have a more extensive endoplasmic reticulum (ER) network than normal B lymphocytes. 10 The abundance of ER membranes in CLL cells has also been noted in earlier investigations and suggests that ER function may be very important for their survival. Consequently, this or...

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“…The ability of BFA to induce apoptosis independent of p53 status has also been noted in other types of malignant cells. 74,75 In contrast, Figure 5. Brefeldin A inhibits VEGF secretion.…”

Section: Discussionmentioning

confidence: 89%

Targeting endoplasmic reticulum protein transport: a novel strategy to kill malignant B cells and overcome fludarabine resistance in CLL

Carew

Nawrocki

Krupnik

et al. 2006

Blood

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“…As brefeldin A may be toxic to cells (Pommepuy et al, 2003), an experiment was carried out to determine the optimum time of incubation after adding brefeldin A. Cells from 5 normal human donors were incubated for 6 h with CEF or PPD, then for a further 6 h or 18 h with brefeldin A.…”

Section: Resultsmentioning

confidence: 99%

MIG (CXCL9) is a more sensitive measure than IFN-γ of vaccine induced T-cell responses in volunteers receiving investigated malaria vaccines

Berthoud¹,

Dunachie²,

Todryk³

et al. 2009

Journal of Immunological Methods

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For many years the IFN-γ ex vivo ELISPOT has been a major assay for assessing human T-cell responses generated by malaria vaccines. The ELISPOT assay is a sensitive assay, but an imperfect correlate of protection against malaria. Monokine induced by gamma (MIG), or CXCL9, is a chemokine induced by IFN-γ and has the potential to provide amplification of the IFN-γ signal. MIG secretion could provide a measure of bio-active IFN-γ and a functional IFN-γ signalling pathway. We report that detecting MIG by flow cytometry and by RT-PCR can be more sensitive than the detection of IFN-γ using these methods. We also find that there is little inter-individual variability in MIG secretion when detected by flow cytometry and that the MIG assay may be used to estimate the amount of bio-active IFN-γ present. Measurement of MIG alongside IFN-γ may provide a fuller picture of Th1 type responses post-vaccination.

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“…BFA treated cells failed to express MT1-MMP on the cell surface and showed increased GRP78 expression, suggesting that abrogated protein trafficking leads to ERSR activation. Pommepuy et al observed increased apoptotic glioma cell death after exposure to BFA [102] (Fig. 2).…”

Section: Targeting Ersr With Small Molecules To Cause Cell Deathmentioning

confidence: 93%

“…The accumulation of these unshuttled proteins in the ER activates ERSR [100, 101]. Apoptosis has been shown to occur in glioma cells following BFA treatment [102]. BFA has also been investigated in glioma cells and shown to downregulate membrane type 1 matrix metalloproteinase (MT1-MMP), an enzyme involved in glioma invasion and metastasis [103].…”

Section: Targeting Ersr With Small Molecules To Cause Cell Deathmentioning

confidence: 99%

Stressed to Death: Targeting Endoplasmic Reticulum Stress Response Induced Apoptosis in Gliomas

Johnson

White²,

Grimaldi³

2011

Current Pharmaceutical Design

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Glial tumors are the main primary adult brain tumor. Even with the most advanced treatments, which include stereotactic microscope aided surgical resection, internal and external radiation therapy and local and systemic chemotherapy, median survival time for patients diagnosed with these malignancies is about 12 months. We explore here the possibility that the endoplasmic reticulum stress response (ERSR) could be a possible target to develop chemotherapeutic agents to induce toxicity in glioma cells. ERSR has the dual capacity of activating repair and/or cytotoxic mechanisms. ERSR is triggered by the accumulation of unfolded proteins in the ER. The presence of unfolded proteins in the ER regulates, via a complex biochemical cascade, the upregulation of molecular chaperones, inhibition of protein synthesis, and an increase of proteasome mediated unfolded protein degradation. ERSR in particular conditions can also contribute to cell death via activation of programmed cell death. Apoptosis activation during ERSR is usually caused by the activation of one or a combination of three biochemical cascades. Induction of these pathways ultimately leads to caspase 3 activation culminating in apoptosis. Glioma cells are in a condition of constant low grade ERSR, which possibly contributes to their resistance to treatment protocols. It is conceivable that small molecules that interact with this phenomenon ultimately could be used to modulate the system to activate apoptosis and cause gliotoxicity. We will discuss here ERSR biochemically relevant features to death mechanisms and already identified small molecules that by modulating ERSR are able to activate glioma cell death.

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Brefeldin A Induces Apoptosis and Cell Cycle Blockade in Glioblastoma Cell Lines

Cited by 20 publications

References 31 publications

Targeting endoplasmic reticulum protein transport: a novel strategy to kill malignant B cells and overcome fludarabine resistance in CLL

Targeting endoplasmic reticulum protein transport: a novel strategy to kill malignant B cells and overcome fludarabine resistance in CLL

MIG (CXCL9) is a more sensitive measure than IFN-γ of vaccine induced T-cell responses in volunteers receiving investigated malaria vaccines

Stressed to Death: Targeting Endoplasmic Reticulum Stress Response Induced Apoptosis in Gliomas

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