Dehydrocostus lactone inhibits NLRP3 inflammasome activation by blocking ASC oligomerization and prevents LPS-mediated inflammation in vivo.

Uncontrolled activation of NLRP3 inflammasome initiates a series of human inflammatory diseases. Targeting NLRP3 inflammasome has attracted considerable attention in developing potential therapeutic interventions. Here, we reported that dehydrocostus lactone (DCL), a main component of Saussurea lappa from the traditional Chinese medicine, inhibited NLRP3 inflammasome-mediated caspase-1 activation and subsequent interleukin (IL)-1ß production in primary mouse macrophages and human peripheral blood mononuclear cells and exerted an inhibitory effect on NLRP3-driven inflammation. Mechanistically, DCL significantly blocked the ASC oligomerization, which is essential for the assembly of activated inflammasome. Importantly, in vivo experiments showed that DCL reduced IL-1ß secretion and peritoneal neutrophils recruitment in LPS-mediated inflammation mouse model, which is demonstrated to be NLRP3 dependent. These results suggest that DCL is a potent pharmacological inhibitor of NLRP3 inflammasome and may be developed as a therapeutic drug for treating NLRP3-associated diseases.

Pinin protects astrocytes from cell death after acute ischemic stroke via maintenance of mitochondrial anti-apoptotic and bioenergetics functions.

BACKGROUND: Stroke is the second most common cause of deaths worldwide. After an ischemic stroke, the proliferated reactive astrocytes in the peri-infarct areas play a beneficial role in neuronal survival. As such, astrocytes have gradually become a target for neuroprotection in stroke. The present study assessed the hypothesis that Pinin (Pnn), originally identified as a nuclear and desmosome-associated protein and is now known to possess anti-apoptotic capacity, protects astrocytes from cell death after ischemic stroke and delineated the underlying mechanisms. METHODS: In in vivo experiments, adult male Sprague-Dawley rats (12-week old) were used to induce acute focal cerebral ischemia employing the middle cerebral artery occlusion (MCAO) method. In in vitro experiments, postnatal day 1 (P1) Sprague-Dawley rat pups were used to prepare cultures of primary astrocytes. Oxygen-glucose deprivation (OGD) and re-oxygenation (OGD/R) procedures were employed to mimic the hypoxic-ischemic condition of stroke in those astrocytes. RESULTS: We found in the peri-infarct area of the ipsilateral cortex and striatum in Sprague-Dawley rats after transient MCAO an increase in Pnn expression that correlated positively with the time-course of infarction as detected by T2-weighted imaging and triphenyltetrazolium chloride staining, augmented number of reactive astrocytes that double-labelled with Pnn as determined by immunofluorescence, and enhanced cytotoxic edema as revealed by diffusion weighted imaging; but mirrored the decreased cleaved caspase-3 as measured by western blot. In an OGD and OGD/R model using primary cultured astrocytes, treatment with Pnn siRNA doubled the chance of surviving astrocytes to manifest cell death as revealed by flow cytometry, and blunted activated ERK signaling, reduced Bcl-2 expression and augmented cleaved caspase 3 detected by western blot in the normoxia, OGD or OGD/R group. Gene-knockdown of Pnn also impeded the reversal from decline in cell viability, elevation in lactate dehydrogenase leakage and decrease in ATP production in the OGD/R group. CONCLUSION: We conclude that the endogenous Pnn participates in neuroprotection after acute ischemic stroke by preserving the viability of astrocytes that survived the ischemic challenge via maintenance of mitochondrial anti-apoptotic and bioenergetics functions.

Glycyrrhizin attenuates hepatic ischemia-reperfusion injury by suppressing HMGB1-dependent GSDMD-mediated kupffer cells pyroptosis.

Gasdermin D (GSDMD), a genetic substrate for inflammatory caspases, plays a central role in pyroptosis of macrophages and release of interleukin­1ß (IL-1ß), but was mainly referred to microbial infection. High mobility group box-1 (HMGB1), served as an alarm molecule during various pathological process, has been widely recognized to be involved in liver ischemia-reperfusion (I/R). Glycyrrhizin, a natural anti-inflammatory and antiviral triterpene in clinical use, was recently referred to have ability to prevent I/R induced liver injury by inhibiting HMGB1 expression and activity. However, the mechanisms responsible for damage amelioration subsequently to HMGB1 inhibition during liver I/R remain enigmatic. This study was designed to explore the functional role and molecular mechanism of glycyrrhizin in the regulation of I/R induced liver injury. We found that liver I/R promotes GSDMD-mediated pyroptotic cell death of Kupffer cells, which was inhibited by glycyrrhizin. Interestingly, endogenous HMGB1, not exogenous one, was involved in hypoxia-reoxygenation (H/R) induced pyroptosis. Moreover, GSDMD knockdown protects kupffer cells against H/R induced pyroptosis in vitro. Here, we report, for the first time, that glycyrrhizin attenuated tissue damage and kupffer cells pyroptosis during liver ischemia-reperfusion injury (LIRI) and identify a previously unrecognized HMGB1- dependent GSDMD- mediated signaling pathway in the mechanism of kupffer cells pyroptosis induced by H/R. Our findings provide the first demonstration of GSDMD-determined pyroptotic cell death responsible for I/R induced release of IL-1ß and this would provide a mandate to better understand the unconventional mechanisms of cytokine release in the sterile innate immune system.

Anticancer effect of ethanol Lycium barbarum (Goji berry) extract on human breast cancer T47D cell line.

The anticancer activity of ethanol extract isolated from Goji berry (EEGB) on T47D human breast cancer cell line has been reported. Cell viability and cell proliferation were examined with the use of BrdU, MTT and NR methods. Induction of apoptosis was assessed by propidium iodide and Hoechst 33342 staining. Expression of genes involved in cell proliferation, apoptosis, cell cycle control and regulation of transcription was estimated using Western blotting analysis. EEGB inhibited the proliferation of breast cancer cells in a time-, and dose-dependent manner. The study confirmed the lack of EEGB cytotoxic activity to normal human skin fibroblasts. Western blot analysis demonstrated an increase in pro-apoptotic and a decrease in anti-apoptotic proteins' expression in cells treated with the extract. Anticancer activity and lack of toxicity against normal cells indicate a chemopreventive potential of Goji berries in breast cancer treatment.

BAG3 protects against hyperthermic stress by modulating NF-κB and ERK activities in human retinoblastoma cells.

PURPOSE: BCL2-associated athanogene 3 (BAG3), a co-chaperone of HSP70, is a cytoprotective and anti-apoptotic protein that acts against various stresses, including heat stress. Here, we examined the effect of BAG3 on the sensitivity of human retinoblastoma cells to hyperthermia (HT). METHODS: We examined the effects of BAG3 knockdown on the sensitivity of Y79 and WERI-Rb-1cells to HT (44 °C, 1 h) by evaluating apoptosis and cell proliferation using western blotting, real-time quantitative PCR (qPCR), flow cytometry, and a WST-8 assay kit. Furthermore, we examined the effects of activating nuclear factor-kappa B (NF-κB) and extracellular signal-regulated kinase (ERK) using western blotting and real time qPCR. RESULTS: HT induced considerable apoptosis along with the activation of caspase-3 and chromatin condensation. The sensitivity of Y79 and WERI-Rb-1 cells to HT was significantly enhanced by BAG3 knockdown. Compared to HT alone, the combination of BAG3 knockdown and HT reduced phosphorylation of the inhibitors of kappa B α (IκBα) and p65, a subunit of NF-κB, and degraded IκB kinase γ (IKKγ) during the recovery period after HT. Furthermore, BAG3 knockdown increased the HT-induced phosphorylation of ERK after HT treatment, and the ERK inhibitor U0126 significantly improved the viability of the cells treated with a combination of BAG3 knockdown and HT. CONCLUSIONS: The silencing of BAG3 seems to enhance the effects of HT, at least in part, by maintaining HT-induced inactivity of NF-κB and the phosphorylation of ERK. These findings indicate that BAG3 may be a potential molecular target for modifying the outcomes of HT in retinoblastoma.

Inhibition of Bcl-2 antiapoptotic members by obatoclax potently enhances sorafenib-induced apoptosis in human myeloid leukemia cells through a Bim-dependent process.

Interactions between the multikinase inhibitor sorafenib and the BH3-mimetic obatoclax (GX15-070) were examined in human acute myeloid leukemia (AML) cells. Treatment with sorafenib/obatoclax induced pronounced apoptosis in and reduced the clonogenic growth of multiple AML lines and primary AML cells but not normal CD34(+) cells. Sorafenib triggered rapid and pronounced Mcl-1 down-regulation accompanied by enhanced binding of Bim to Bcl-2 and Bcl-xL, effects that were abolished by obatoclax coadministration. Notably, shRNA knockdown of Bim, Bak, or Bax, but not Noxa, significantly attenuated obatoclax/sorafenib lethality, whereas ectopic expression of Mcl-1 exerted a protective effect. Furthermore, exposure of leukemia cells to sorafenib and obatoclax markedly induced autophagy, reflected by rapid and pronounced LC3 processing and LC3-green fluorescent protein (GFP) punctate formation. Multiple autophagy inhibitors or VPS34 knockdown, significantly potentiated sorafenib/obatoclax lethality, indicating a cytoprotective role for autophagy in this setting. Finally, studies in a xenograft mouse model revealed that combined sorafenib/obatoclax treatment markedly reduced tumor growth and significantly prolonged survival in association with Mcl-1 down-regulation and apoptosis induction, whereas agents administered individually had only modest effects. These findings suggest that combining sorafenib with agents that inhibit Mcl-1 and Bcl-2/Bcl-xL such as obatoclax may represent a novel and potentially effective strategy in AML.

Autophagy, protein aggregation and hyperthermia: a mini-review.

PURPOSE: We aim to explore the role of macroautophagy in cellular responses to hyperthermia. Protein damage incurred during hyperthermia can either lead to cell death or may be repaired by polypeptide quality control pathways including: (1) the deterrence of protein unfolding by molecular chaperones and (2) proteolysis of the denatured proteins within the proteasome. A third pathway of protein quality control is triggered by formation of protein aggregates in the heat shocked cell. This is the macroautophagy pathway in which protein aggregates are transported to specialised organelles called autolysosomes capable of degrading the aggregates. The consequences for cell viability of triggering this pathway are complex and may involve cell death, although under many circumstances, including exposure of cells to hyperthermia, autophagy leads to enhanced cell survival. We have discussed mechanisms by which cells detect protein aggregates and recruit them into the macroautophagy pathway as well as the potential role of inhibiting this process in hyperthermia. CONCLUSIONS: Directed macroautophagy, with its key role in protein quality control, seems an attractive target for a therapy such as hyperthermia that functions principally through denaturing the proteome. However, much work is needed to decode the mechanisms of thermal stress-mediated macroautophagy and their role in survival/death of cancer cells before recommendations can be made on targeting this pathway in combination with hyperthermia.

Targeted knockdown of death-associated protein kinase expression induces TRAIL-mediated apoptosis in human endometrial adenocarcinoma cells.

Death-associated protein kinase (DAPK) is a serine/threonine kinase that participates in the modulation of apoptosis and tumor suppression. Our previous study revealed high levels of DAPK protein expression in differentiated endometrial adenocarcinoma cells. To clarify the role of DAPK in human endometrial adenocarcinomas, we down-regulated endogenous DAPK expression in HHUA cells, a well-differentiated endometrial adenocarcinoma cell line, using specific small-interfering RNAs (siRNAs). The suppression of endogenous DAPK expression triggered apoptosis in HHUA cells, as evidenced by an increase in the sub-G1 DNA content in flow cytometric analyses. The apoptosis induced by the DAPK siRNA transfections was caspase-dependent, as characterized by the activations of caspase-3, -8 and -9. RNase protection assays detected higher levels of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), DR4 and DR5 transcripts in the DAPK siRNA-transfected HHUA cells than in the control siRNA-transfected cells. Consistent with these findings, enzyme-linked immunosorbent assays revealed that the DAPK siRNA transfections significantly increased the secretion of TRAIL protein from the cells. Treatment with recombinant human TRAIL protein dose-dependently suppressed the cell viability of HHUA cells. The present findings reveal that down-regulation of endogenous DAPK expression in HHUA cells induces caspase-dependent apoptosis, possibly through increased TRAIL, DR4 and DR5 signaling, thereby suggesting that DAPK expression is essential for HHUA cell survival. Consequently, endogenous DAPK mRNA may represent a potential candidate for molecularly targeted anticancer therapies.

Epigallocatechin-3-gallate induces cell death in acute myeloid leukaemia cells and supports all-trans retinoic acid-induced neutrophil differentiation via death-associated protein kinase 2.

Acute promyelocytic leukaemia (APL) patients are successfully treated with all-trans retinoic acid (ATRA). However, concurrent chemotherapy is still necessary and less toxic therapeutic approaches are needed. Earlier studies suggested that in haematopoietic neoplasms, the green tea polyphenol epigallocatechin-3-gallate (EGCG) induces cell death without adversely affecting healthy cells. We aimed at deciphering the molecular mechanism of EGCG-induced cell death in acute myeloid leukaemia (AML). A significant increase of death-associated protein kinase 2 (DAPK2) levels was found in AML cells upon EGCG treatment paralleled by increased cell death that was significantly reduced upon silencing of DAPK2. Moreover, combined ATRA and EGCG treatment resulted in cooperative DAPK2 induction and potentiated differentiation. EGCG toxicity of primary AML blasts correlated with 67 kDa laminin receptor (67LR) expression. Pretreatment of AML cells with ATRA, causing downregulation of 67LR, rendered these cells resistant to EGCG-mediated cell death. In summary, it was found that (i) DAPK2 is essential for EGCG-induced cell death in AML cells, (ii) ATRA and EGCG cotreatment significantly boosted neutrophil differentiation, and 67LR expression correlates with susceptibility of AML cells to EGCG. We thus suggest that EGCG, by selectively targeting leukaemic cells, may improve differentiation therapies for APL and chemotherapy for other AML subtypes.

Corchorusin-D, a saikosaponin-like compound isolated from Corchorus acutangulus Lam., targets mitochondrial apoptotic pathways in leukemic cell lines (HL-60 and U937).

PURPOSE: The presence of triterpene saponins in Corchorus acutangulus Lam. has been reported. However, no studies concerning biological activity of the plant extracts have been done so far. In the present study, the anti-leukemic activity of the methanol extract of aerial parts (ME) of C. acutangulus has been investigated, and efforts have been made to identify the active ingredient responsible for this activity. METHODS: The anti-leukemic activity of ME, its fractions and corchorusin-D (COR-D), the active ingredient, was investigated in leukemic cell lines U937 and HL-60 using cell viability and MTT assays. The molecular pathways leading to the activity of COR-D were examined by confocal microscopy, flow-cytometry, caspase and Western blot assays. RESULTS: ME, its n-butanolic fraction and COR-D inhibited cell growth and produced significant cytotoxicity in leukemic cell lines U937 and HL-60. COR-D produced apoptotic cell death via mitochondrial disfunction and was found to pursue the intrinsic pathway by inciting the release of apoptosis-inducing factors (AIFs) from mitochondria. COR-D-induced translocation of Bax from cytosol to mitochondria facilitating caspase-9 activation and up regulation of downstream pathways leading to caspase-3 activation and PARP cleavage, which resulted in the subsequent accumulation of cells in the sub-G0 phase followed by DNA fragmentation. CONCLUSIONS: COR-D possesses significant anti-leukemic activity in U937 and HL-60 cell lines by acting on the mitochondrial apoptotic pathways. Since the necrotic body formation is low after COR-D treatment, the occurrence of inflammation in in vivo systems could be reduced, which represents a positive indication in view of therapeutic application.

Baicalin administration is effective in positive regulation of twenty-four ischemia/reperfusion-related proteins identified by a proteomic study.

Baicalin is a major plant polyphenolic compound derived from the dried root of Scutellaria baicalensis Georgi, a Traditional Chinese Medicine material. The current study applied proteomics to investigate the different protein expression modes in mice brains after middle cerebral artery occlusion (MCAO) with or without administration of baicalin. Twenty-four proteins which had a 3-fold change in abundance compared to the sham control sample were selected to be identified. Statistical analysis demonstrated that there was no significant difference in expression between the twenty-four proteins baicalin-treated MCAO group and the sham-operation group (n=24, p=0.102). Gene Ontology analysis linked these proteins to fifteen biological processes, including cellular process, developmental process and biological regulation. Results indicated that baicalin performed well in regulating proteins in energy metabolism but had a relatively weak effect in the regulation of proteins in neurogenesis and apoptosis. In sum, our findings suggest baicalin may be a potential therapeutic agent in treating stroke and may also be a strong candidate for future research in its actions on individual proteins.

Gtdap-1 promotes autophagy and is required for planarian remodeling during regeneration and starvation.

Remodeling is an integral component of tissue homeostasis and regeneration. In planarians, these processes occur constantly in a simple tractable model organism as part of the animal's normal life history. Here, we have studied the gene Gtdap-1, the planarian ortholog of human death-associated protein-1 or DAP-1. DAP-1, together with DAP-kinase, has been identified as a positive mediator of programmed cell death induced by gamma-IFN in HeLa cells. Although the function of DAP-kinase is well characterized, the role of DAP-1 has not been studied in detail. Our findings suggest that Gtdap-1 is involved in autophagy in planarians, and that autophagy plays an essential role in the remodeling of the organism that occurs during regeneration and starvation, providing the necessary energy and building blocks to the neoblasts for cell proliferation and differentiation. The gene functions at the interface between survival and cell death during stress-inducing processes like regeneration and starvation in sexual and asexual races of planarians. Our findings provide insights into the complex interconnections among cell proliferation, homeostasis, and cell death in planarians and perspectives for the understanding of neoblast stem cell dynamics.

Mechanisms involved in Korean mistletoe lectin-induced apoptosis of cancer cells.

AIM: To investigate the anti-cancer mechanisms of Korean mistletoe lectin (Viscum album coloratum agglutinin, VCA) using a human colon cancer cell line (COLO). METHODS: Cytotoxic effects of VCA on COLO cells were determined by 3- (4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide (MTT) assay in vitro and tumor-killing effects in vivo. To study the mechanisms involved, the expression of various pro-caspases, anti-apoptotic proteins, and death receptors was determined by western blot. To determine which death receptor is involved in VCA-induced apoptosis of COLO cells, cytotoxicity was examined by MTT assay after treatment with agonists or antagonists of death receptors. RESULTS: VCA killed COLO cells in a time- and dose-dependent manner and induced complete regression of tumors in nude mice transplanted with COLO cells. Treatment of COLO cells with VCA activated caspase-2, -3, -8, and -9 and decreased expression of anti-apoptotic molecules including receptor interacting protein, nuclear factor-kappaB, X-linked inhibitor of apoptosis protein, and Akt/protein kinase B. We then examined the involvement of death receptors in VCA-induced apoptosis. Only tumor necrosis factor receptor 1, among the death receptors examined, was involved in apoptosis of COLO cells, evidenced by inhibition of VCA-induced apoptosis and decreased activation of caspases, particularly caspase-8, by tumor necrosis factor receptor 1 antagonizing antibody. CONCLUSION: VCA-induced apoptotic COLO cell death is due to the activation of caspases and inhibition of anti-apoptotic proteins, in part through the tumor necrosis factor receptor 1 signaling pathway.

Genomic and proteomic screening of apoptosis mitochondrial regulators for drug target discovery.

Screening strategies of therapeutic molecules and targets have received increasing attention during the past few years. Indeed, identification of novel compounds and drug targets involved in apoptosis control is a major rate-limiting step in anticancer drug development efforts. In this review, we discuss the current screening methodologies to discover novel potential therapeutics targets and drugs implicated in the apoptotic pathway, in particular the intrinsic pathway. In addition, we present a proteomic screening strategy that led us to identify a mitochondrial glutathione-S-transferase as a novel regulator of the pro-apoptotic adenine nucleotide translocase pore function.

Abolition of the tapetum suicide program ruins microsporogenesis.

Microsporogenesis in angiosperms takes places within the anther. Microspores are surrounded by a layer of cells, the tapetum, which degenerates during the later stages of pollen development with cytological features characteristic of programmed cell death (PCD). We report herein that the expression of AtBI-1, which suppresses Bax-induced cell death, in the tapetum at the tetrad stage inhibits tapetum degeneration and subsequently results in pollen abortion, while activation of AtBI-1 at the later stage does not. Our results demonstrate that the PCD signal commences at the tetrad stage and that the proper timing of PCD in the tapetum is essential for normal microsporogenesis.

A peroxisome proliferator-activated receptor-gamma agonist, troglitazone, facilitates caspase-8 and -9 activities by increasing the enzymatic activity of protein-tyrosine phosphatase-1B on human glioma cells.

Despite dramatic advances in adjuvant therapies, patients with malignant glioma face a bleak prognosis. Because many adjuvant therapies seek to induce glioma apoptosis, strategies that lower thresholds for the induction of apoptosis may improve patient outcomes. Therefore, elucidation of the biological mechanisms that underlie resistance to current therapies is needed to develop new therapeutic strategies. Here we proposed a novel mechanism of proapoptotic effect induced by a pharmacological peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist, troglitazone, that facilitates caspase signaling in human glioma cells. Troglitazone activates protein-tyrosine phosphatase (PTP)-1B, which subsequently reduces phosphotyrosine 705 STAT3 (pY705-STAT3) via a PPARgamma-independent pathway. Reduction of pY705-STAT3 in glioma cells caused down-regulation of FLIP (FADD-like IL-1beta-converting enzyme-inhibitory protein) and Bcl-2. Furthermore, troglitazone induced Ser-392 phosphorylation of p53 via a PPARgamma-dependent pathway and up-regulation of Bax in a p53 wild-type glioma. When given with tumor necrosis factor-related apoptosis-inducing ligand or caspase-dependent chemotherapeutic agents, such as etoposide and paclitaxel, troglitazone exhibited a synergistic effect by facilitating caspase-8/9 activities. A PPARgamma antagonist, GW9662, did not block this effect, although a PTP inhibitor abrogated it. Knockdown of STAT3 by STAT3-small interfering RNA negated the inhibitory effect of PTP inhibitor on troglitazone, indicating that troglitazone uses a STAT3 inactivation mechanism that makes caspase-8/9 activities susceptible to cytotoxic agents in glioma cells and that PTP1B plays a critical role in the down-regulation of activated STAT3, as well as FLIP and Bcl-2. When taken with caspase-dependent anti-neoplastic agents, troglitazone may be a promising drug for use against malignant gliomas because it facilitates the caspase cascade, thereby lowering thresholds for the apoptosis induction of glioma cells.

Introduction of in vitro transcribed ENO1 mRNA into neuroblastoma cells induces cell death.

BACKGROUND: Neuroblastoma is a solid tumour of childhood often with an unfavourable outcome. One common genetic feature in aggressive tumours is 1p-deletion. The alpha-enolase (ENO1) gene is located in chromosome region 1p36.2, within the common region of deletion in neuroblastoma. One alternative translated product of the ENO1 gene, known as MBP-1, acts as a negative regulator of the c-myc oncogene, making the ENO1 gene a candidate as a tumour suppressor gene. METHODS: Methods used in this study are transfection of cDNA-vectors and in vitro transcribed mRNA, cell growth assay, TUNEL-assay, real-time RT-PCR (TaqMan) for expression studies, genomic sequencing and DHPLC for mutation detection. RESULTS: Here we demonstrate that transfection of ENO1 cDNA into 1p-deleted neuroblastoma cell lines causes' reduced number of viable cells over time compared to a negative control and that it induces apoptosis. Interestingly, a similar but much stronger dose-dependent reduction of cell growth was observed by transfection of in vitro transcribed ENO1 mRNA into neuroblastoma cells. These effects could also be shown in non-neuroblastoma cells (293-cells), indicating ENO1 to have general tumour suppressor activity. Expression of ENO1 is detectable in primary neuroblastomas of all different stages and no difference in the level of expression can be detected between 1p-deleted and 1p-intact tumour samples. Although small numbers (11 primary neuroblastomas), there is some evidence that Stage 4 tumours has a lower level of ENO1-mRNA than Stage 2 tumours (p = 0.01). However, mutation screening of 44 primary neuroblastomas of all different stages, failed to detect any mutations. CONCLUSION: Our studies indicate that ENO1 has tumour suppressor activity and that high level of ENO1 expression has growth inhibitory effects.

[The Bcl-2 family of proteins as drug targets]. / Antagonistes de Bcl-2, thérapies anticancéreuses alternatives.

Programmed cell death or apoptosis is a crucial process for normal embryonic development and homeostasis. Apoptosis is known to be coupled to multiple signalling pathways. Identification of critical points in the regulation of apoptosis is of major interest both for the understanding of control of cell fate and for the discovery of new pharmacological targets, particularly in oncology. Indeed, defects in the execution of apoptosis are known to participate in tumour initiation and progression as well as in chemoresistance. The Bcl-2 family members constitute essential intracellular players in the apoptotic machinery. Those proteins are either pro or anti-apoptotic, they interact with each other to regulate apoptosis. Inhibiting the heterodimerisation between pro- and anti-apoptotic members is sufficient to promote apoptosis in mammalian cells. Small molecules, antagonists or peptidomimetics inhibiting this heterodimerisation, represent a therapeutic prototype targeting the apoptotic cascade. They induce cell death by activating directly the mitochondrial apoptotic pathway. Considerable evidence indicate that such Bcl-2 antagonists could be useful drugs to induce apoptosis preferentially in neoplastic cells.