Selective anticancer effects of a synthetic flavagline on human Oct4-expressing cancer stem-like cells via a p38 MAPK-dependent caspase-3-dependent pathway

Emhemmed, Fathi; Azouaou, Sarah Ali; Thuaud, Frédéric; Schini‐Kerth, Valérie B.; Désaubry, Laurent; Muller, Christian D.; Fuhrmann, Gregor

doi:10.1016/j.bcp.2014.02.020

Cited by 19 publications

(15 citation statements)

References 38 publications

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“…Indeed, rooperol treatment of teratocarcinomal cells led to a dramatic increase of the expression of cleaved caspase-3, the main executor of stress-induced apoptosis. This upregulation was associated with a strong downregulation of Oct4, suggesting that such kind of drug could target the stemness factor via a caspase-3-dependent process as we observed previously [10].…”

Section: Discussionsupporting

confidence: 52%

“…Oct4 activity is enhanced when it interacts with two additional transcription factors, Nanog and Sox2 [16]. There are several lines of evidences that induction of apoptosis in pluripotent normal or potential cancer stem-like cells is accompanied by a downregulation of Oct4 [2,[8][9][10]. We therefore analyzed the expression levels of Oct4, Nanog and Sox2 during rooperolinduced apoptosis of teratocarcinomal stem-like cells.…”

Section: Resultsmentioning

confidence: 99%

“…Alternatively, we and others, previously argued that the malignant counterparts of embryonic stem cell lines, like the embryonal carcinoma stem cell lines, are suitable models of CSCs [1,8,9]. These cell lines are poorly differentiated pluripotent germinal stem cells which express different stemness markers and have a high aggressive malignant phenotype; they can therefore be used as experimental tools for carcinogenicity studies and the evaluation of potential anticancer chemopreventive agents [1,10].…”

Section: Introductionmentioning

confidence: 96%

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Selective ROS-dependent p53-associated anticancer effects of the hypoxoside derivative rooperol on human teratocarcinomal cancer stem-like cells

et al. 2014

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Cancer stem cells (CSCs) are potential targets for innovative anticancer therapies that involve natural products with potential chemopreventive effects. We therefore analyzed the antineoplastic activity of rooperol, the aglycone of the plant-derived compound hypoxoside, on a model of Oct4-expressing cancer stem-like cell, i.e. the human embryonal carcinoma (EC) cell NT2/D1. Rooperol selectively inhibited the proliferation of NT2/D1 cells in a concentration-dependent manner and had no effect on either normal embryonic fibroblasts which are more restrictive pluripotent stem cells or on NCCIT p53-mutant EC cells. Accordingly, rooperol only eliminates colon carcinoma cells expressing p53. Rooperol treatment triggered cell death on NT2/D1 cells through the alteration of mitochondrial membrane potential and production of reactive oxygen species (ROS). Rooperol-induced apoptosis was associated with activation of p53 and concentration-dependent changes of the expression levels of both caspase 3 and poly ADP ribose polymerase type 1 cleaved subunits. These modifications were accompanied by a downregulation of Oct4 and its two partners involved in the maintenance of cell pluripotency and self-renewal, Nanog and Sox2.Treatment with intracellular membrane permeant O2 (-) scavengers prevented rooperol-induced apoptosis and upregulation of the expression of p53 and active caspase-3. Our findings indicate that rooperol mediates its growth inhibitory effects on CSCs via a mitochondrial redox-sensitive mechanism. We propose that abrogating the expression of the stemness regulators is a prerequisite for rooperol to fully exert its pro-apoptotic properties on wild-type p53-bearing CSCs.

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Section: Discussionsupporting

confidence: 52%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

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Selective ROS-dependent p53-associated anticancer effects of the hypoxoside derivative rooperol on human teratocarcinomal cancer stem-like cells

et al. 2014

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“…These results suggest that our compounds may have the ability to stimulate reprogramming of AsPC-1 cells independently of any pro-apoptotic activity, and thus should be further studied by following the expression of other CSC phenotype markers like Oct4, Nanog or Sox2. 81 Activity on tumor spheroids. Tumor spheroids are 3D culture models that in vitro mimic in vivo malignant tissue in respect to multiple parameters such as drug concentration, molecular weight, kinetics, charge, solubility, diffusion, oxygenation, metabolism, and sequestration.…”

Section: 80mentioning

confidence: 99%

Quinoline based mono- and bis-(thio)carbohydrazones: synthesis, anticancer activity in 2D and 3D cancer and cancer stem cell models

Božić

Marinković

Bjelogrlić³

et al. 2016

RSC Adv.

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A comparative study of antitumor activity of mono-and bis-quinoline based (thio)carbohydrazones was investigated by a series of tests on two human malignant cell lines: acute monocytic leukemia (THP-1) and pancreatic adenocarcinoma cancer stem cells (AsPC-1). Thiocarbohydrazones (TCHs) revealed superior pro-apoptotic activity over carbohydrazones (CHs) on both tested cell phenotypes, also displaying multi-target profile activities. Programmed cell death triggered by TCHs was partially caspasedependent, mainly caspase-8 related. Activity against cancer stem cells (CSCs) was evaluated on 2D monolayers and 3D spheroidal models, where two out of three tested bis-TCHs successfully stimulated apoptosis accompanied by a reduction in size of treated spheres. Additionally, all bis-TCHs induced significant decrease in percentage of CD44-expressing AsPC-1 cells that indicate on their ability to induce reprogramming of CSC phenotype. Current results highly support further assessment of bisTCHs in order to specify their specific targets in cancer cells and particularly in the CSCs subpopulation.

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“…Articles by using constitutive active mutants (20), gene knockout (21), and pharmacological inhibitors (22). The siRNA knockdown experiments presented here clearly established the role of MKP-1 in the regulation of LPS-induced apoptosis in rIEC-6 enterocytes.…”

Section: Mkp-1 Protects Against Apoptosismentioning

confidence: 99%

Mitogen-activated protein kinase phosphatase-1 prevents lipopolysaccharide-induced apoptosis in immature rat intestinal epithelial cells

et al. 2015

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Background: Necrotizing enterocolitis is characterized by intestinal inflammation and epithelial barrier dysfunction. Mitogen-activated protein kinase (MAPK) phosphatase (MKP)-1 plays a pivotal role in the feedback control of MAPK signaling, which regulates inflammation and apoptosis. We hypothesized that MKP-1 prevents lipopolysaccharide (LPS)-induced apoptosis in intestinal epithelial cells. Methods: Western blot analysis and qPCR were used to assess MKP-1, MAPK (p38, extracellular signal-regulated kinase (ERK), and c-Jun N terminal kinases (JNK)), caspase 3, caspase 9, tumor necrosis factor (TNF)-α, and cyclooxygenase (COX)-2 expression levels in rIEC-6 enterocytes. MKP-1 expression was inhibited using small interfering RNA (siRNA) methodology. Viable cell number was determined using trypan blue exclusion. results: LPS stimulation led to activation of p38, JNK, and ERK, and induction of MKP-1 mRNA and protein expression. The induction of MKP-1 was associated with a decrease in p38 phosphorylation, and knockdown of MKP-1 prolonged p38 phosphorylation. While LPS stimulation significantly attenuated proliferation of rIEC-6 cells transfected with scramble siRNA, LPS stimulation resulted in a net decrease in viable cell number in cells transfected with MKP-1 siRNA. Following LPS stimulation, MKP-1 knockdown resulted in greater caspase 3 and 9 activities and greater proinflammatory cytokine (TNF-α, COX-2) expression than in cells transfected with scramble siRNA. conclusion: Our results demonstrate that MKP-1 has a central role in preventing inflammation-induced apoptosis in rIEC-6 enterocytes.

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Selective anticancer effects of a synthetic flavagline on human Oct4-expressing cancer stem-like cells via a p38 MAPK-dependent caspase-3-dependent pathway

Cited by 19 publications

References 38 publications

Selective ROS-dependent p53-associated anticancer effects of the hypoxoside derivative rooperol on human teratocarcinomal cancer stem-like cells

Selective ROS-dependent p53-associated anticancer effects of the hypoxoside derivative rooperol on human teratocarcinomal cancer stem-like cells

Quinoline based mono- and bis-(thio)carbohydrazones: synthesis, anticancer activity in 2D and 3D cancer and cancer stem cell models

Mitogen-activated protein kinase phosphatase-1 prevents lipopolysaccharide-induced apoptosis in immature rat intestinal epithelial cells

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