Search results for " cell death"

Cytomegalovirus vector expressing RAE-1γ induces enhanced anti-tumor capacity of murine CD8+ T cells

2017

Designing of CD8 T cell vaccines which would provide protection against tumors is still considered a great challenge in immunotherapy. Here we show a robust potential of a cytomegalovirus (CMV) vector expressing the NKG2D ligand RAE-1γ as CD8 T cell-based vaccine against malignant tumors. Immunization with the CMV vector expressing RAE-1γ delayed tumor growth or even provided complete protection against tumor challenge in both prophylactic and therapeutic settings. Moreover, a potent tumor control in mice vaccinated with this vector can be further enhanced by blocking the immune checkpoints TIGIT and PD-1. Expression of RAE-1γ by the CMV vector potentiated expansion of KLRG1+ CD8 T cells wi…

Biological Effect of a Hybrid Anticancer Agent Based on Kinase and Histone Deacetylase Inhibitors on Triple-Negative (MDA-MB231) Breast Cancer Cells

2016

We examined the effects of the histone deacetylase inhibitor (HDACi) suberoylanilide\ud hydroxamic acid (SAHA) combined with the vascular endothelial growth factor receptor-1/2 inhibitor\ud (3Z)-5-hydroxy-3-(1H-pyrrol-2-ylmethylidene)-2,3-dihydro-1H-indol-2-one on MDA-MB-231 breast\ud cancer cells (triple-negative) in the form of both a cocktail of the separate compounds and a chemically\ud synthesized hybrid (N-hydroxy-N'-[(3Z)-2-oxo-3-(1H-pyrrol-2-ylmethylidene)-2,3-dihydro-1H-indol-\ud 5-yl]octanediamide). Comparative flow cytometric and Western blot analyses were performed on\ud cocktail- and hybrid-treated cells to evaluate cell cycle distribution, autophagy/apoptosis modulation,\ud an…

7-ketocholesterol and 7β-hydroxycholesterol: in vitro and animal models used to characterize their activities and to identify molecules preventing th…

2020

International audience; Oxysterols are molecules derived by the oxidation of cholesterol and can be formed either by auto-oxidation, enzymatically or by both processes. Among the oxysterols formed by auto-oxidation, 7-ketocholesterol and 7beta-hydroxycholesterol are the main forms generated. These oxysterols, formed endogenously and brought in large quantities by certain foods, have major cytotoxic properties. They are powerful inducers of oxidative stress, inducing dysfunction of organelles (mitochondria, lysosomes and peroxisomes) that can cause cell death. These molecules are often identified in increased amounts in common pathological states such as cardiovascular diseases, certain eye …

Combined HAT/EZH2 modulation leads to cancer-selective cell death

2018

Contains fulltext : 197351.pdf (Publisher’s version ) (Open Access) Epigenetic alterations have been associated with both pathogenesis and progression of cancer. By screening of library compounds, we identified a novel hybrid epi-drug MC2884, a HAT/EZH2 inhibitor, able to induce bona fide cancer-selective cell death in both solid and hematological cancers in vitro, ex vivo and in vivo xenograft models. Anticancer action was due to an epigenome modulation by H3K27me3, H3K27ac, H3K9/14ac decrease, and to caspase-dependent apoptosis induction. MC2884 triggered mitochondrial pathway apoptosis by up-regulation of cleaved-BID, and strong down-regulation of BCL2. Even aggressive models of cancer, …

The role of Ca(2+) in cell death caused by oxidative glutamate toxicity and ferroptosis

2018

Ca(2+) ions play a fundamental role in cell death mediated by oxidative glutamate toxicity or oxytosis, a form of programmed cell death similar and possibly identical to other forms of cell death like ferroptosis. Ca(2+) influx from the extracellular space occurs late in a cascade characterized by depletion of the intracellular antioxidant glutathione, increases in cytosolic reactive oxygen species and mitochondrial dysfunction. Here, we aim to compare oxidative glutamate toxicity with ferroptosis, address the signaling pathways that culminate in Ca(2+) influx and cell death and discuss the proteins that mediate this. Recent evidence hints toward a role of the machinery responsible for stor…

2017

Neuronal degeneration following traumatic brain injury (TBI) leads to intracellular accumulation of dysfunctional proteins and organelles. Autophagy may serve to facilitate degradation to overcome protein debris load and therefore be an important pro-survival factor. On the contrary, clearing may serve as pro-death factor by removal of essential or required proteins involved in pro-survival cascades. Sequestosome 1 (SQSTM1/p62) is a main regulator of the autophagic pathway that directs ubiquinated cargoes to autophagosomes for degradation. We show that SQSTM1 protein levels are suppressed 24 h and by trend 5 days after trauma. In line with these data the expression of Sqstm1 mRNA is reduced…

Prognostic significance of circulating PD-1, PD-L1, pan-BTN3As, BTN3A1 and BTLA in patients with pancreatic adenocarcinoma

2019

PDAC is one of the most heterogeneous cancers with low chemotherapeutic sensitivity due to a dense stroma, a weak vasculature and significant biological aggressivity. In cancer, suppressive immune checkpoints are often hyper-activated to ensure an effective evasion of tumor cells from immune surveillance. These immune checkpoints include in part, the B7/butyrophilin-like receptors such as butyrophilin sub-family 3A/CD277 receptors (BTN3A), the B and T lymphocyte attenuator (BTLA) belonging to the B7-like receptors and the programmed death protein (PD-1) with its ligand PD-L1. We evaluated the plasma level of these markers in 32 PDAC patients (learning cohort) by ad hoc developed ELISA’s and…

The Unfolded Protein Response Plays a Predominant Homeostatic Role in Response to Mitochondrial Stress in Pancreatic Stellate Cells.

2016

Activated pancreatic stellate cells (PaSC) are key participants in the stroma of pancreatic cancer, secreting extracellular matrix proteins and inflammatory mediators. Tumors are poorly vascularized, creating metabolic stress conditions in cancer and stromal cells that necessitate adaptive homeostatic cellular programs. Activation of autophagy and the endoplasmic reticulum unfolded protein response (UPR) have been described in hepatic stellate cells, but the role of these processes in PaSC responses to metabolic stress is unknown. We reported that the PI3K/mTOR pathway, which AMPK can regulate through multiple inputs, modulates PaSC activation and fibrogenic potential. Here, using primary a…

Innovative Therapy, Monoclonal Antibodies and Beyond

2017

IF 6.794; International audience; The seventh Edition of "Innovative Therapy, Monoclonal Antibodies and Beyond" Meeting took place in Milan, Italy, on January 27, 2017. The two sessions of the meeting were focused on: 1) Preclinical assays and novel biotargets; and 2) monoclonal antibodies, cell therapies and targeted molecules. Between these two sessions, a lecture entitled "HLA-antigens modulation and response to immune checkpoint inhibitor immunotherapy" was also presented. Despite the impressive successes in cancer immunotherapy in recent years, the response to immune based interventions occurs only in a minority of patients (∼20%). Several basic and translational mechanisms of resistan…

Phytochemicals Approach for Developing Cancer Immunotherapeutics

2017

Phytochemicals or their derived compounds are being increasingly recognized as potentially potent complementary treatments for cancer. Among them, some phytochemicals are being actively evaluated for use as adjuvants in anticancer therapies. For instance, shikonin and hypericin were found to induce immunogenic cell death (ICD) of specific cancer cells, and this effect was able to further activate the recognition activity of tumor cells by the host immune system. On the other hand, some derivatives of phytochemicals, such as dihydrobenzofuran lignan (Q2-3) have been found to induce the secretion of an endogenous anticancer factor, namely IL-25, from non-malignant cells. These findings sugges…