COX-2–Independent Effects of Celecoxib Sensitize Lymphoma B Cells to TRAIL-Mediated Apoptosis

Gallouët, Anne-Sophie; Travert, Marion; Bresson, Lucie; Guilloton, Fabien; Pangault, Céline; Caulet‐Maugendre, Sylvie; Lamy, Thierry; Tarte, Karin; Guillaudeux, Thierry

doi:10.1158/1078-0432.ccr-13-2305

Cited by 36 publications

(27 citation statements)

References 49 publications

(55 reference statements)

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“…Celecoxib has been described to down‐regulate Mcl‐1 levels (Gallouet et al, ; Song, Chen, & Xing, ). We therefore examined whether celecoxib alone could be responsible for the inhibitory effect on Mcl‐1 expression and the predominantly synergistic anti‐proliferative activity of CUSP9‐LD/ABT263.…”

Section: Resultsmentioning

confidence: 99%

“…It seemed tempting to identify one individual drug out of CUSP9‐LD that would be responsible for the inhibitory effect on Mcl‐1 expression and the predominantly synergistic anti‐neoplastic activity. Based on the literature, celecoxib was a potential candidate (Gallouet et al, ; Song et al, ). However, at the concentration used within CUSP9‐LD, celecoxib neither decreased expression of Mcl‐1 in our setting nor was it sufficient to achieve similar biological activity when combined with ABT263 alone, compared to the full cocktail.…”

Section: Discussionmentioning

confidence: 99%

“…To this purpose, we used specific siRNA to silence Mcl-1 and observed that Mcl-1 knockdown sensitized A172 glioblastoma cells to the pro-apoptotic effects of ABT263 (Figures 3c,d and S2A). Celecoxib has been described to down-regulate Mcl-1 levels (Gallouet et al, 2014;Song, Chen, & Xing, 2013). We therefore examined whether celecoxib alone could be responsible for the inhibitory effect on Mcl-1 expression and the predominantly synergistic antiproliferative activity of CUSP9-LD/ABT263.…”

Section: Selective Inhibition Of Mcl-1 Enhances Abt263-mediated Apomentioning

confidence: 99%

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Bcl‐2/Bcl‐xL inhibition predominantly synergistically enhances the anti‐neoplastic activity of a low‐dose CUSP9 repurposed drug regime against glioblastoma

Halatsch¹,

Kast²,

Dwucet³

et al. 2019

British J Pharmacology

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Background and Purpose Drug repurposing represents a promising approach to safely accelerate the clinical application of therapeutics with anti‐cancer activity. In this study, we examined whether inhibition of the anti‐apoptotic Bcl‐2 family proteins Bcl‐2 and Bcl‐xL enhances the biological effects of the repurposed CUSP9 regimen in an in vitro setting of glioblastoma. Experimental Approach We applied 3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyltetrazolium bromide assays to assess cellular proliferation. Annexin V/propidium iodide and tetramethylrhodamine, ethyl ester staining were used to examine apoptosis. Western blotting, RT‐PCR, and specific knockdown experiments using siRNA were employed to examine molecular mechanisms of action. Key Results Bcl‐2/Bcl‐xL inhibition exerted synergistic anti‐proliferative effects across established, primary cultured, and stem‐like glioblastoma cells when combined with CUSP9 which had been reduced to only one tenth of its proposed original concentration (CUSP9‐LD). The combination treatment also led to enhanced apoptosis with loss of mitochondrial membrane potential and activation of caspases. On the molecular level, CUSP9‐LD counteracted ABT263‐mediated up‐regulation of Mcl‐1. Silencing of Mcl‐1 enhanced ABT263‐mediated apoptosis which indicates that down‐regulation of Mcl‐1 is crucial for the induction of cell death by the combination treatment. Conclusion and Implications These data suggest that Bcl‐2/Bcl‐xL inhibition enhances the susceptibility of glioblastoma cells towards CUSP9, allowing dramatic dose reduction and potentially decreased toxicity when applied clinically. A clinical trial involving the original CUSP doses (CUSP9v3) is currently ongoing in our institution (NCT02770378). The Bcl‐2/Bcl‐xL inhibitor ABT263 is in clinical trials and might represent a valuable adjunct to the original CUSP.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Selective Inhibition Of Mcl-1 Enhances Abt263-mediated Apomentioning

confidence: 99%

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Bcl‐2/Bcl‐xL inhibition predominantly synergistically enhances the anti‐neoplastic activity of a low‐dose CUSP9 repurposed drug regime against glioblastoma

Halatsch¹,

Kast²,

Dwucet³

et al. 2019

British J Pharmacology

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“…In addition, celecoxib promotes the apoptotic activity of TRAIL contributing to TRAILmediated cell death 61 . Similarly, 71.6% of DLBCL cases showed a remarkable expression of COX2, and there was a correlation between COX2 and VEGF-A expression (a main factor of angiogenesis) confirming the potential role of angiogenesis in the DLBCL malignancy.…”

Section: Role Of Inflammation In Tumor Promotionmentioning

confidence: 99%

Role of the tumor microenvironment in regulating apoptosis and cancer progression

et al. 2016

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Apoptosis is a gene-directed program that is engaged to efficiently eliminate dysfunctional cells. Evasion of apoptosis may be an important gate to tumor initiation and therapy resistance. Like any other developmental program, apoptosis can be disrupted by several genetic aberrations driving malignant cells into an uncontrolled progression and survival. For its sustained growth, cancer develops in a complex environment, which provides survival signals and rescues malignant cells from apoptosis. Recent studies have clearly shown a wide interaction between tumor cells and their microenvironment, confirming the influence of the surrounding cells on tumor expansion and invasion. These non-malignant cells not only intensify tumor cells growth but also upgrade the process of metastasis. The strong crosstalk between malignant cells and a reactive microenvironment is mediated by soluble chemokines and cytokines, which act on tumor cells through surface receptors. Disturbing the microenvironment signaling might be an encouraging approach for patient's treatment. Therefore, the ultimate knowledge of "tumor-microenvironment" interactions facilitates the identification of novel therapeutic procedures that mobilize cancer cells from their supportive cells. This review focuses on cancer progression mediated by the dysfunction of apoptosis and by the fundamental relationship between tumor and reactive cells. New insights and valuable targets for cancer prevention and therapy are also presented.

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“…16 The clinical development of protein-based TRAIL therapeutics has been stymied following clinical efficacy results in lead indications that were less robust than anticipated, despite a benign safety profile. The limited clinical activity of these TRAIL-based agents has been ascribed to intrinsic tumor cell attributes such as O-glycosylation enzymes, 17,18 the tumor microenvironment, 19,20 and limitations of the therapeutic agents themselves such as suboptimal death receptor clustering and poor chemical characteristics. 21 Nonetheless, TRAIL possesses ideal therapeutic properties as an endogenous, natural, anti-cancer protein that was evolved as part of the immune system.…”

Section: Introductionmentioning

confidence: 99%

ONC201 induces cell death in pediatric non-Hodgkin's lymphoma cells

Talekar¹,

Allen

Dicker

et al. 2015

Cell Cycle

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Abbreviations: TRAIL, TNF-related apoptosis-inducing ligand; DR5, death receptor 5; TNF, tumor necrosis family; NHL, non-Hodgkin's lymphoma.ONC201/TIC10 is a small molecule initially discovered by its ability to coordinately induce and activate the TRAIL pathway selectively in tumor cells and has recently entered clinical trials in adult advanced cancers. The anti-tumor activity of ONC201 has previously been demonstrated in several preclinical models of cancer, including refractory solid tumors and a transgenic lymphoma mouse model. Based on the need for new safe and effective therapies in pediatric non-Hodgkin's lymphoma (NHL) and the non-toxic preclinical profile of ONC201, we investigated the in vitro efficacy of ONC201 in non-Hodgkin's lymphoma (NHL) cell lines to evaluate its therapeutic potential for this disease. ONC201 caused a dose-dependent reduction in the cell viability of NHL cell lines that resulted from induction of apoptosis. As expected from prior observations, induction of TRAIL and its receptor DR5 was also observed in these cell lines. Furthermore, dual induction of TRAIL and DR5 appeared to drive the observed apoptosis and TRAIL expression was correlated linearly with sub-G1 DNA content, suggesting its potential role as a biomarker of tumor response to ONC201-treated lymphoma cells. We further investigated combinations of ONC201 with approved chemotherapeutic agents used to treat lymphoma. ONC201 exhibited synergy in combination with the anti-metabolic agent cytarabine in vitro, in addition to cooperating with other therapies. Together these findings indicate that ONC201 is an effective TRAIL pathway-inducer as a monoagent that can be combined with chemotherapy to enhance therapeutic responses in pediatric NHL.

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COX-2–Independent Effects of Celecoxib Sensitize Lymphoma B Cells to TRAIL-Mediated Apoptosis

Cited by 36 publications

References 49 publications

Bcl‐2/Bcl‐xL inhibition predominantly synergistically enhances the anti‐neoplastic activity of a low‐dose CUSP9 repurposed drug regime against glioblastoma

Bcl‐2/Bcl‐xL inhibition predominantly synergistically enhances the anti‐neoplastic activity of a low‐dose CUSP9 repurposed drug regime against glioblastoma

Role of the tumor microenvironment in regulating apoptosis and cancer progression

ONC201 induces cell death in pediatric non-Hodgkin's lymphoma cells

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