The anti-caspase inhibitor Q-VD-OPH prevents AIDS disease progression in SIV-infected rhesus macaques.

Apoptosis has been proposed as a key mechanism responsible for CD4+ T cell depletion and immune dysfunction during HIV infection. We demonstrated that Q-VD-OPH, a caspase inhibitor, inhibits spontaneous and activation-induced death of T cells from SIV-infected rhesus macaques (RMs). When administered during the acute phase of infection, Q-VD-OPH was associated with (a) reduced levels of T cell death, (b) preservation of CD4+/CD8+ T cell ratio in lymphoid organs and in the gut, (c) maintenance of memory CD4+ T cells, and (d) increased specific CD4+ T cell response associated with the expression of cytotoxic molecules.

IL-2 immunotherapy in chronically SIV-infected Rhesus macaques.

Background: Despite inducing a sustained increase in CD4+ T cell counts, intermittent recombinant IL-2 (rIL-2) therapy did not confer a better clinical outcome in HIV-infected patients enrolled in large phase III clinical trials ESPRIT and SILCAAT. Several hypotheses were evoked to explain these discrepancies. Here, we investigated the impact of low and high doses of IL-2 in Rhesus macaques of Chinese origin infected with SIVmac251 in the absence of antiretroviral therapy (ART).

Notch activation on effector T cells increases their sensitivity to Treg cell-mediated suppression through upregulation of TGF-βRII expression.

Notch proteins play an important role in embryonic development and cell-fate decisions. Notch influences also the activation and differentiation of peripheral T cells. Here, we investigated whether Notch signaling modulates the response of effector T cells to regulatory T (Treg) cells.

Two overlapping domains of a lyssavirus matrix protein that acts on different cell death pathways.

The lyssavirus matrix (M) protein induces apoptosis. The regions of the M protein that are essential for triggering cell death pathways are not yet clearly defined. We therefore compared the M proteins from two viruses that have contrasting characteristics in terms of cellular apoptosis: a genotype 3 lyssavirus, Mokola virus (MOK), and a genotype 1 rabies virus isolated from a dog from Thailand (THA).

Oxaliplatin-mediated inhibition of survivin increases sensitivity of head and neck squamous cell carcinoma cell lines to paclitaxel.

The present study deals with the evaluation of the efficacy of oxaliplatin and paclitaxel combination as a potential strategy in controlling HNSCC cell proliferation and the assessment of correlation between occurrence of apoptosis and changes in expression of survivin (IAP). The panel cell lines included two HNSCC cell lines (Cal27 and NT8e) and one normal cell line (293) with differential level of survivin expression in accordance with chemosensitivity. The cytotoxicity and effect of drugs on apoptosis was determined, separately and in combination.

A chemical inhibitor of Apaf-1 exerts mitochondrioprotective functions and interferes with the intra-S-phase DNA damage checkpoint.

QM31 represents a new class of cytoprotective agents that inhibit the formation of the apoptosome, the caspase activation complex composed by Apaf-1, cytochrome c, dATP and caspase-9. Here, we analyzed the cellular effects of QM31, as compared to the prototypic caspase inhibitor Z-VAD-fmk. QM31 was as efficient as Z-VAD-fmk in suppressing caspase-3 activation, and conferred a similar cytoprotective effect.

Apaf-1 Deficiency Causes Chromosomal Instability.

Apaf-1 is an essential component of the apoptosome, the molecular complex assembled in response to mitochondrial cytochrome c release that promotes caspase activation. Apaf-1 expression is suppressed in some malignant tumors, in particular melanoma as well as cervical and colorectal carcinoma, in which the loss of Apaf-1 expression marks tumor progression and poor prognosis. Recent results from our laboratory demonstrate that Apaf-1 has an apoptosis-unrelated function that may well account for its role as a tumor suppressor.

Nonapoptotic role for Apaf-1 in the DNA damage checkpoint.

Apaf-1 is an essential factor for cytochrome c-driven caspase activation during mitochondrial apoptosis but has also an apoptosis-unrelated function. Knockdown of Apaf-1 in human cells, knockout of apaf-1 in mice, and loss-of-function mutations in the Caenorhabditis elegans apaf-1 homolog ced-4 reveal the implication of Apaf-1/CED-4 in DNA damage-induced cell-cycle arrest. Apaf-1 loss compromised the DNA damage checkpoints elicited by ionizing irradiation or chemotherapy.

Selective resistance of tetraploid cancer cells against DNA damage-induced apoptosis.

Aneuploidy and chromosomal instability, which are frequent in cancer, can result from the asymmetric division of tetraploid precursors. Genomic instability may favor the generation of more aggressive tumor cells with a reduced propensity for undergoing apoptosis. To assess the impact of tetraploidization on apoptosis regulation, we generated a series of stable tetraploid HCT116 and RKO colon carcinoma cell lines.

Phosphoprotein enriched in astrocytes-15 kDa expression inhibits astrocyte migration by a protein kinase C delta-dependent mechanism.

Phosphoprotein enriched in astrocytes-15 kDa (PEA-15), a phosphoprotein enriched in astrocytes, inhibits both apoptosis and proliferation in normal and cancerous cells. Here, analysis of PEA-15 expression in glioblastoma organotypic cultures revealed low levels of PEA-15 in tumor cells migrating away from the explants, regardless of the expression levels in the originating explants. Because glioblastomas are highly invasive primary brain tumors that can originate from astrocytes, we explored the involvement of PEA-15 in the control of astrocyte migration.

Enrichment of non-synchronized cells in the G1, S and G2 phases of the cell cycle for the study of apoptosis.

The susceptibility of cells to apoptosis induction is deeply influenced by their position in the cell cycle. Unfortunately, however, current methods for the enrichment of cells in defined phases of the cell cycle are mostly based on the synchronization of cells by agents or conditions that are intrinsically toxic and induce apoptosis on their own. We developed a novel procedure for the purification of cells in distinct phases of the cell cycle.

Apoptosis regulation in tetraploid cancer cells.

Tetraploidy can result in cancer-associated aneuploidy. As shown here, freshly generated tetraploid cells arising due to mitotic slippage or failed cytokinesis are prone to undergo Bax-dependent mitochondrial membrane permeabilization and subsequent apoptosis. Knockout of Bax or overexpression of Bcl-2 facilitated the survival of tetraploid cells at least as efficiently as the p53 or p21 knockout.

EBV infection of human B lymphocytes leads to down-regulation of Bim expression: relationship to resistance to apoptosis.

EBV infects a large proportion of the human population worldwide and is one of the major viruses with human B lymphocyte tropism. It can immortalize human B lymphocytes and controls their resistance to apoptosis. EBV infection is associated with several lymphomas, including Burkitt's lymphoma.

B cell receptor-mediated apoptosis of human lymphocytes is associated with a new regulatory pathway of Bim isoform expression.

Studies in Bim-deficient mice have shown that the proapoptotic molecule Bim plays a key role in the control of B cell homeostasis and activation. However, the role of Bim in human B lymphocyte apoptosis is unknown. We show in this study that, depending on the degree of cross-linking, B cell receptors can mediate both Bim-dependent and apparent Bim-independent apoptotic pathways.

Differential modulation of interleukin-2-and interleukin-4-mediated early activation of normal human B lymphocytes by the caspase inhibitor zVAD-fmk.

Caspases are a group of cysteine-related proteases that control the process of apoptosis and may also be involved in the control of lymphocyte activation. We show here that the broad-spectrum caspase inhibitor benzyloxycarbonyl (Cbz)-Val-Ala-Asp (Ome)-fluoromethylketone (zVAD-fmk) prevents the proliferation of resting human B tonsilar lymphocytes mediated by the B cell mitogen SAC or the combination of anti-mu Ab and IL-2. zVAD-fmk inhibits IL-2-induced phosphorylation of the retinoblastoma protein, and cyclin D2 expression.

p38-mediated regulation of an Fas-associated death domain protein-independent pathway leading to caspase-8 activation during TGFbeta-induced apoptosis in human Burkitt lymphoma B cells BL41.

On binding to its receptor, transforming growth factor beta (TGFbeta) induces apoptosis in a variety of cells, including human B lymphocytes. We have previously reported that TGFbeta-mediated apoptosis is caspase-dependent and associated with activation of caspase-3. We show here that caspase-8 inhibitors strongly decrease TGFbeta-mediated apoptosis in BL41 Burkitt's lymphoma cells.

Cdk2 associates with MAP kinase in vivo and its nuclear translocation is dependent on MAP kinase activation in IL-2-dependent Kit 225 T lymphocytes.

Cell proliferation is controlled by cdk2 which in association with cyclin E and A regulates G1/S transition and S phase progression. cdk2 activation is dependent on its localization in the nucleus where regulatory mediators are found. We report that activation of cdk2 is associated with the formation of cdk2/MAP Kinase complexes.