The Anti-Tumor Effect of HDAC Inhibition in a Human Pancreas Cancer Model Is Significantly Improved by the Simultaneous Inhibition of Cyclooxygenase 2

Peulen, Olivier; Gonzalez, Arnaud; Peixoto, Paul; Turtoï, Andrei; Mottet, Denis; Delvenne, Philippe; Castronovo, Vincenzo

doi:10.1371/journal.pone.0075102

Cited by 37 publications

(43 citation statements)

References 61 publications

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“…In this study, we focused on COX-2 and HDAC as therapeutic targets, both of which were highly expressed in high-grade bladder cancer (3, 4, 7). Previously, Peulen and colleagues reported that combined treatment with the HDAC inhibitor MS-275 and the COX-2 inhibitor celecoxib induced G 1 cell-cycle arrest against pancreatic cancer cells in vitro (14). On the other hand, in the present study, the combined treatment with a novel HDAC inhibitor, OBP-801, and celecoxib synergistically inhibited cell growth of high-grade bladder cancer cells in vitro by enhancing apoptosis (Fig.…”

Section: Discussionsupporting

confidence: 47%

A Histone Deacetylase Inhibitor, OBP-801, and Celecoxib Synergistically Inhibit the Cell Growth with Apoptosis via a DR5-Dependent Pathway in Bladder Cancer Cells

Toriyama

Horinaka

Yasuda

et al. 2016

Molecular Cancer Therapeutics

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The prognosis of muscle-invasive bladder cancer with metastasis is poor. There have been no therapeutic improvements for many years, and an innovative therapy for muscle-invasive bladder cancer has been awaited to replace the conventional cytotoxic chemotherapy. Here, we show a candidate method for the treatment of bladder cancer. The combined treatment with a novel histone deacetylase (HDAC) inhibitor, OBP-801, and celecoxib synergistically inhibited cell growth and markedly induced apoptosis through the caspase-dependent pathway in high-grade bladder cancer cells. Furthermore, the combined treatment induced expression of death receptor 5 (DR5). We identified that knockdown of DR5 by small interfering RNA (siRNA) significantly suppressed apoptosis by the combined treatment. Therefore, we conjectured that the apoptosis induced by OBP-801 and celecoxib is at least partially dependent on DR5. However, it was interesting that the combined treatment drastically suppressed expression of DR5 ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). These data suggest that there is no involvement of TRAIL in the induction of apoptosis by the combination, regardless of the dependence of DR5. Moreover, xenograft studies using human bladder cancer cells showed that the combined therapy suppressed tumor growth by upregulating expressions of DR5 and Bim. The inhibition of tumor growth was significantly more potent than that of each agent alone, without significant weight loss. This combination therapy provided a greater benefit than monotherapy in vitro and in vivo. These data show that the combination therapy with OBP-801 and celecoxib is a potential novel therapeutic strategy for patients with muscle-invasive bladder cancer. Mol Cancer Ther; 15(9); 2066-75. Ó2016 AACR.

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Section: Discussionsupporting

confidence: 47%

A Histone Deacetylase Inhibitor, OBP-801, and Celecoxib Synergistically Inhibit the Cell Growth with Apoptosis via a DR5-Dependent Pathway in Bladder Cancer Cells

Toriyama

Horinaka

Yasuda

et al. 2016

Molecular Cancer Therapeutics

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“…17 We selected the widely used BxPC-3 cells for their ability to grow on CAM. This anti-tumor growth effect was associated with a massive inhibition of capillaries development within the tumoral stroma, suggesting a loss of proangiogenic activities of the cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…In order to visualize the tumor vasculature, tumors sections have been subjected to FITC-conjugated SNA (Sambucus nigra agglutinin) staining as previously described. 17 Densitometric profiling and quantification were performed using ImageJ (Rasband, W.S., ImageJ V1.48, U. S. National Institutes of Health, Bethesda, Maryland, http:// imagej.nih.gov/ij/, 1997-2014).…”

Section: Ultrastructural Analysismentioning

confidence: 99%

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Myoferlin plays a key role in VEGFA secretion and impacts tumor‐associated angiogenesis in human pancreas cancer

Fahmy

Gonzalez

Arafa

et al. 2015

Intl Journal of Cancer

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Pancreatic ductal adenocarcinoma is one of the most deadly forms of cancers with no satisfactory treatment to date. Recent studies have identified myoferlin, a ferlin family member, in human pancreas adenocarcinoma where its expression was associated to a bad prognosis. However, the function of myoferlin in pancreas adenocarcinoma has not been reported. In other cell types, myoferlin is involved in several key plasma membrane processes such as fusion, repair, endocytosis and tyrosine kinase receptor activity. In this study, we showed that myoferlin silencing in BxPC-3 human pancreatic cancer cells resulted in the inhibition of cell proliferation in vitro and in a significant reduction of the tumor volume in chick chorioallantoic membrane assay. In addition to be smaller, the tumors formed by the myoferlin-silenced cells showed a marked absence of functional blood vessels. We further demonstrated that this effect was due, at least in part, to an inhibition of VEGFA secretion by BxPC-3 myoferlin-silenced cells. Using immunofluorescence and electron microscopy, we linked the decreased VEGFA secretion to an impairment of VEGFA exocytosis. The clinical relevance of our results was further strengthened by a significant correlation between myoferlin expression in a series of human pancreatic malignant lesions and their angiogenic status evaluated by the determination of the blood vessel density.

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“…However, previously it has been shown that the long-term maintenance in culture of PDAC cell lines, such as BxPC-3, CFPAC-1 and PANC-1 cells 33,34 , resulted in distinct and irreversible loss of crucial genetic and biologic properties. This included the occurrence of distinct stem cell populations and complex genomic aberrations, affecting critical signaling pathways 35,36 .…”

Section: Discussionmentioning

confidence: 99%

Development of bioluminescent chick chorioallantoic membrane (CAM) models from primary pancreatic cancer cells: A platform for drug testing

León

Rovithi

Avan³

et al. 2017

Pancreatology

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The aim of the present study was to develop chick-embryo chorioallantoic membrane (CAM) bioluminescent tumor models employing low passage cell cultures obtained from primary pancreatic ductal adenocarcinoma (PDAC) cells. Primary PDAC cells transduced with lentivirus expressingFirefly-luciferase (Fluc) were established and inoculated onto the CAM membrane, with >80% engraftment. Fluc signal reliably correlated with tumor growth. Tumor features were evaluated by immunohistochemistry and genetic analyses, including analysis of mutations and mRNA expression of PDAC pivotal genes, as well as microRNA (miRNA) profiling. These studies showed that CAM tumors had histopathological and genetic characteristic comparable to the original tumors. We subsequently tested the modulation of key miRNAs and the activity of gemcitabine and crizotinib on CAM tumors, showing that combination treatment resulted in 63% inhibition of tumor growth as compared to control (p < 0.01). These results were associated with reduced expression of miR-21 and increased expression of miR-155. Our study provides the first evidence that transduced primary PDAC cells can form tumors on the CAM, retaining several histopathological and (epi)genetic characteristics of original tumors. Moreover, our results support the use of these models for drug testing, providing insights on molecular mechanisms underlying antitumor activity of new drugs/combinations.With less than 7% of patients alive five years after diagnosis, pancreatic ductal adenocarcinoma (PDAC) exhibits one of the poorest prognoses of all solid tumors. Despite extensive clinical efforts, the outcome of this malignancy has not improved in the last decade, and PDAC is expected to become the second deadliest cancer, after lung cancer, by 2030 1,2 .Gaining more insight into the mechanisms that delineate tumor progression in PDAC could ultimately provide more successful therapeutic approaches. To this end, genetically engineered mouse models (GEMMs) have provided a powerful tool, developing tumors that recapitulate both the underlying biology and the dense desmoplastic reaction of PDACs. This stromal reaction has been considered for years as one of the mediators of resistance to chemotherapy 3 . However, experimental and clinical evidence demonstrated that anti-stromal approaches may favour PDAC aggressiveness, reinforcing the need to critically revisit the complexity of cancer-stroma interactions for translational and pharmacological implications 4 . Recent studies suggested that early passages of primary PDAC cells and "avatar" mice can mimic the genetic diversity that characterizes the human disease and might be better predictors of drug activity, including the standard treatment with gemcitabine 5,6 .Despite several studies used such in vivo models in order to promote drug development and selection, their costs and complexity impaired the translation of these results in the clinical setting. Novel, cost-effective models that similarly mimic tumor biology and provide faster information on the activ...

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The Anti-Tumor Effect of HDAC Inhibition in a Human Pancreas Cancer Model Is Significantly Improved by the Simultaneous Inhibition of Cyclooxygenase 2

Cited by 37 publications

References 61 publications

A Histone Deacetylase Inhibitor, OBP-801, and Celecoxib Synergistically Inhibit the Cell Growth with Apoptosis via a DR5-Dependent Pathway in Bladder Cancer Cells

A Histone Deacetylase Inhibitor, OBP-801, and Celecoxib Synergistically Inhibit the Cell Growth with Apoptosis via a DR5-Dependent Pathway in Bladder Cancer Cells

Myoferlin plays a key role in VEGFA secretion and impacts tumor‐associated angiogenesis in human pancreas cancer

Development of bioluminescent chick chorioallantoic membrane (CAM) models from primary pancreatic cancer cells: A platform for drug testing

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