PubMed Health⌕ Search

Biomedical subjects

Eric Solary

Publications and source records attributed to Eric Solary.

At least 37 records · Page 2Linked to original sources
PubMed2004

Translocation of the inhibitor of apoptosis protein c-IAP1 from the nucleus to the Golgi in hematopoietic cells undergoing differentiation: a nuclear export signal-mediated event.

The caspase inhibitor and RING finger-containing protein cellular inhibitor of apoptosis protein 1 (c-IAP1) has been shown to be involved in both apoptosis inhibition and signaling by members of the tumor necrosis factor (TNF) receptor family. The protein is regulated transcriptionally (eg, is a target for nuclear factor-kappaB [NF-kappaB]) and can be inhibited by mitochondrial proteins released in the cytoplasm upon apoptotic stimuli. The present study indicates that an additional level of regulation of c-IAP1 may be cell compartmentalization. The protein is present in the nucleus of undifferentiated U937 and THP1 monocytic cell lines. When these cells undergo differentiation under phorbol ester exposure, c-IAP1 translocates to the cytoplasmic side of the Golgi apparatus. This redistribution involves a nuclear export signal (NES)-mediated, leptomycin B-sensitive mechanism. Using site-directed mutagenesis, we localized the functional NES motif in the caspase recruitment domain (CARD) of c-IAP1. A nucleocytoplasmic redistribution of the protein was also observed in human monocytes as well as in tumor cells from epithelial origin when undergoing differentiation. c-IAP1 does not translocate from the nucleus of cells whose differentiation is blocked (ie, in cell lines and monocytes from transgenic mice overexpressing B-cell lymphoma 2 [Bcl-2] and in monocytes from patients with chronic myelomonocytic leukemia). Altogether, these observations associate c-IAP1 cellular location with cell differentiation, which opens new perspectives on the functions of the protein.

Active Transport, Cell Nucleus↗
PubMed2004

Cisplatin-induced CD95 redistribution into membrane lipid rafts of HT29 human colon cancer cells.

We have shown previously that the death receptor CD95 could contribute to anticancer drug-induced apoptosis of colon cancer cells. In addition, anticancer drugs cooperate with CD95 cognate ligand or agonistic antibodies to trigger cancer cell apoptosis. In the present study, we show that the anticancer drug cisplatin induces clustering of CD95 at the surface of the human colon cancer cell line HT29, an event inhibited by the inhibitor of acid sphingomyelinase (aSMase) imipramine. The cholesterol sequestering agent nystatin also prevents cisplatin-induced CD95 clustering and decreases HT29 cell sensitivity to cisplatin-induced apoptosis and the synergy between cisplatin and anti-CD95 agonistic antibodies. CD95, together with the adaptor molecule Fas-associated death domain and procaspase-8, is redistributed into cholesterol- and sphingolipid-enriched cell fractions after cisplatin treatment, suggesting plasma membrane raft involvement. Interestingly, nystatin prevents the translocation of the aSMase to the extracellular surface of plasma membrane and the production of ceramide, suggesting that these early events require raft integrity. In addition, nystatin prevents cisplatin-induced transient increase in plasma membrane fluidity that could be required for CD95 translocation. Together, these results demonstrate that cisplatin activates aSMase and induces ceramide production, which triggers the redistribution of CD95 into the plasma membrane rafts. Such redistribution contributes to cell death and sensitizes tumor cells to CD95-mediated apoptosis.

Antineoplastic Agents↗
PubMed2004

Increased immunogenicity of colon cancer cells by selective depletion of cytochrome C.

We and others have previously reported in an in vivo rat colon cancer cell model that cell death precedes and is necessary for the development of a specific antitumoral immune response. To sensitize colon cancer cells to death, we depleted cytochrome c by stable transfection with an antisense construct. Cytochrome c depletion sensitizes human and rat colon cancer cells to a nonapoptotic, nonautophagic death induced by various stimuli. This increased sensitization to a necrosis-like cell death may be related to a decrease in cellular ATP levels and an increase in reactive oxygen species production caused by cytochrome c depletion. In vivo, depletion of cytochrome c decreases the tumorigenicity of colon cancer cells in syngeneic rats without influencing their growth in immune-deficient animals. Furthermore, decreased expression of cytochrome c in tumor cells facilitates in vivo "necrotic" cell death and the induction of a specific immune response. These results delineate a novel strategy to sensitize colon cancer cells to chemotherapy and to increase their immunogenicity in immuno-competent hosts.

Animals↗
PubMed2004

Casein kinase II-mediated phosphorylation of NF-kappaB p65 subunit enhances inducible nitric-oxide synthase gene transcription in vivo.

Nitric oxide (NO) produced by inducible nitric-oxide synthase (NOSII) is mainly regulated at the transcriptional level by the nuclear factor-kappaB (NF-kappaB). In the present study, we further analyzed the role of NF-kappaB in the in vivo transcriptional regulation of NOSII gene by comparing two clones isolated from the EMT-6 mouse mammary cancer cell line. In response to interleukin (IL)-1beta or lipopolysaccharide (LPS), EMT-6 clone J (EMT-6J) cells produce 3-fold more NO than EMT-6 clone H (EMT-6H) cells, an effect correlated with enhanced activation of NF-kappaB in EMT-6J cells. In response to IL-1beta, the kinetics of degradation of NF-kappaB inhibitors IkappaB-alpha and IkappaB-beta, the nucleo-cytoplasmic shuttling of the transcription factor and its binding to a specific DNA sequence were similar in both clones. In contrast, an IL-1beta-induced phosphorylation of serine residues in NF-kappaB p65 subunit was observed in EMT-6J, but not in EMT-6H, cells. This IL-1beta-induced phosphorylation of p65 was specifically prevented by pretreatment of EMT-6J cells with the casein kinase II inhibitor DRB. Small interfering RNA-mediated depletion of casein kinase II-alpha subunit also decreased NF-kappaB transcriptional activity and NOSII gene transcription in IL-1beta and LPS-stimulated EMT-6J cells to the levels observed in EMT-6H cells treated in the same conditions. Altogether, these data indicate that casein kinase II-mediated phosphorylation of p65 subunit can enhance the transcriptional activity of NF-kappaB in vivo. This post-translational modification of the transcription factor can be responsible for increased NOSII gene transcription and NO production in tumor cells exposed to either IL-1beta or LPS.

Animals↗
PubMed2004

CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative.

We investigated the mechanisms of immune tolerance raised by tumors by comparing immunogenic and tolerogenic tumor cell clones isolated from a rat colon carcinoma. When injected into syngeneichosts, the immunogenic REGb cells yield tumors that are rejected, while the tolerogenic PROb cells yield progressive tumors and inhibit the regression of REGb tumors. We show here that PROb tumor volume is correlated with an expansion of CD4(+)CD25(+) regulatory T lymphocytes in lymphoid tissues. These cells delay in vivo the rejection of REGb tumors and inhibit in vitro T cell-mediated immune responses against REGb cells through a mechanism that requires cell contact between effector and regulatory T cells and involves TGF-beta. While total T cells fromPROb tumor-bearing rats yield no apparent anti-tumor immune response, depletion of CD25(+) T cells restores this reactivity. A single administration of cyclophosphamide depletes CD4(+)CD25(+) T cells in PROb tumor-bearing animals, delays the growth of PROb tumors, and cures rats bearing established PROb tumors when followed by an immunotherapy which has no curative effect when administered alone. These results demonstrate the role of CD4(+)CD25(+) regulatory T cells in tumor-induced immune tolerance and the interest of regulatory T cell depletion to sensitize established tumors to immunotherapy.

Animals↗
PubMed2004

Analyzing markers of apoptosis in vitro.

Cell death by apoptosis was first identified based on morphological changes reproduced with great fidelity in cells of widely different origin when exposed to a death stimulus. These changes include condensation of the cytosol and the nuclear chromatin, blebbing of the plasma membrane, and cell fragmentation into corpses that are engulfed by neighboring cells. Apoptotic cells demonstrate various levels of DNA fragmentation and exposed phosphatidylserine on the outer leaflet of their plasma membrane. Most apoptotic pathways converge on the mitochondria, inducing the disruption of the mitochondrial trans-membrane potential and the release of soluble molecules from mitochondrial inter-membrane space. One of these molecules is cytochrome c, which, in the cytosol, activates proteases of the caspase family. This chapter suggests methods to identify these characteristic morphological and biochemical events, and cell-free systems that can be used to identify the molecular pathways leading to the death phenotype.

Animals↗
PubMed2004

Topoisomerase I and II inhibitors control caspase-2 pre-messenger RNA splicing in human cells.

We have recently shown that the topoisomerase II inhibitor, etoposide (VP16), could trigger caspase-2 pre-mRNA splicing in human leukemic cell lines. This leads to increased inclusion of exon 9, which is specifically inserted into the short caspase-2S isoform mRNA and absent from the long caspase-2L isoform mRNA. One of the consequences of this alternative splicing is a decrease in the total amount of the mature form of caspase-2L mRNA and protein. In this study, we analyzed the effects of several representative molecules of various classes of cytotoxic agents on caspase-2 pre-mRNA splicing in both U937 leukemic cells and in HeLa cervix carcinoma cells. Very strikingly, both topoisomerase I (camptothecin and homocamptothecin derivatives) and II (VP16, amsacrine, doxorubicin, mitoxantrone) inhibitors induced exon 9 inclusion. DNA intercalating glycosyl indolocarbazole derivatives as well as DNA alkylating agents, such as cisplatin and melphalan, antimetabolites like 5-fluorouracil, and mitotic spindle poisons like vinblastine had no effect. Therefore, both classes of DNA topoisomerases can control pre-mRNA splicing of the caspase-2 transcript. In addition, the splicing reaction brought about by camptothecin was hampered in human CEM/C2 and in murine P388-45R leukemic deficient in topoisomerase I activity. Conversely, VP16 did not trigger caspase-2 alternative splicing in human HL60/MX2 leukemic cells harboring a mutant topoisomerase II. Minigene transfection analysis revealed that topoisomerase inhibitors did not change the splicing profile when cis-acting elements in intron-9, reported to control exon 9 inclusion independently of drug treatment, were removed. Rather, our experiments suggest that exon 9 inclusion induced by topoisomerase inhibitors reflects the activity exerted by topoisomerase I or II on proteins that control splicing reactions, or their direct involvement in pre-mRNA splicing.

Alternative Splicing↗
PubMed2003

Freshly isolated bone marrow cells induce death of various carcinoma cell lines.

In some carcinomas such as digestive tract carcinomas, bone marrow infiltration by tumor cells is a frequent event but usually remains a micrometastatic disease and rarely induces overt bone lesions. The mechanisms responsible for the control of these metastases in the bone marrow remain poorly known. We show that freshly isolated bone marrow cells from human, murine and rat origin rapidly kill a wide range of syngeneic or xenogeneic carcinoma cell lines in culture. Further analysis of this cytotoxic process in the rat indicated that neither resident bone marrow macrophages nor NK cells were responsible for this cytotoxic effect that was restricted to a subpopulation of bone marrow cells expressing CD90 (Thy-1), a marker of hemopoietic precursors. The tumoricidal activity of these cells did not require long-term culture nor addition of exogenous cytokines or growth factors. A subset of CD90+ cells that rapidly differentiates into CD163(ED2)-expressing macrophages was observed to be responsible for tumor cell killing. These macrophages induced a non-apoptotic death of tumor cells, a process that required both a direct interaction with the tumor cell and nitric oxide (NO) production through the activation of inducible nitric oxide-synthase (iNOS). This ability of pluripotent hemopoietic stem cells to rapidly differentiate into macrophages capable of killing invasive tumor cells may account for the limited expansion of micrometastases of some carcinomas in the bone marrow.

Animals↗
PubMed2003

Resveratrol-induced apoptosis is associated with Fas redistribution in the rafts and the formation of a death-inducing signaling complex in colon cancer cells.

Resveratrol, a polyphenol found in grape skin and various other food products, may function as a cancer chemopreventive agent for colon and other malignant tumors and possesses a chemotherapeutic potential through its ability to trigger apoptosis in tumor cells. The present study analyses the molecular mechanisms of resveratrol-induced apoptosis in colon cancer cells, with special attention to the role of the death receptor Fas in this pathway. We show that, in the 10-100 microm range of concentrations, resveratrol activates various caspases and triggers apoptosis in SW480 human colon cancer cells. Caspase activation is associated with accumulation of the pro-apoptotic proteins Bax and Bak that undergo conformational changes and relocalization to the mitochondria. Resveratrol does not modulate the expression of Fas and Fas-ligand (FasL) at the surface of cancer cells, and inhibition of the Fas/FasL interaction does not influence the apoptotic response to the molecule. Resveratrol induces the clustering of Fas and its redistribution in cholesterol and sphingolipid-rich fractions of SW480 cells, together with FADD and procaspase-8. This redistribution is associated with the formation of a death-inducing signaling complex (DISC). Transient transfection of either a dominant-negative mutant of FADD, E8, or MC159 viral proteins that interfere with the DISC function, decreases the apoptotic response of SW480 cells to resveratrol and partially prevents resveratrol-induced Bax and Bak conformational changes. Altogether, these results indicate that the ability of resveratrol to induce the redistribution of Fas receptor in membrane rafts may contribute to the molecule's ability to trigger apoptosis in colon cancer cells.

Apoptosis↗
PubMed2003

Heat shock proteins, cellular chaperones that modulate mitochondrial cell death pathways.

Stress or heat shock proteins (HSPs) are ubiquitous and highly conserved proteins whose expression is induced in response to a wide variety of physiological and environmental insults. They allow the cells to survive to otherwise lethal conditions. Various mechanisms have been proposed to account for the cytoprotective functions of HSPs. These proteins play an essential role in intracellular "house-keeping" by assisting the correct folding of nascent and stress-accumulated misfolded proteins and preventing their aggregation. Several HSPs have also demonstrated to directly interact with various components of the tightly regulated programmed cell death machinery, upstream, and downstream of the mitochondrial events. Finally, HSPs could play a role in the proteasome-mediated degradation of selected proteins under stress conditions. Altogether, these properties could make HSPs appropriate targets for modulating cell death pathways.

Animals↗
PubMed2003

Chemotherapy enhances TNF-related apoptosis-inducing ligand DISC assembly in HT29 human colon cancer cells.

Cytokines such as Fas-ligand (Fas-L) and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) can induce human colon cancer cell apoptosis through engagement of their death domain receptors. All the cancer cells are not sensitive to these cytokines. We have shown recently that low doses of cytotoxic drugs could restore TRAIL-induced cell death in resistant colon cancer cell lines. The present work further explores the death pathway triggered by the cytotoxic drug/TRAIL combination in HT-29 colon cancer cells (www.alexis-corp.com). Clinically relevant concentrations of cisplatin, doxorubicin and 5-fluorouracil synergize with TRAIL to trigger HT-29 cell death. Activation of this pathway leads to apoptosis that involves both caspases and the mitochondria. An increased recruitment of Fas-associated death domain (FADD) and procaspase-8 to the TRAIL-induced death-inducing signaling complex (DISC) was shown in cells exposed to anticancer drugs. Following caspase-8 activation at the DISC level, the mitochondria-dependent death pathway is activated, as demonstrated by the cleavage of Bid, the dissipation of DeltaPsi(m), the release of mitochondrial proteins in the cytosol and the inhibitory effect of Bcl-2 expression. Importantly, besides mitochondrial potentiation, we show here that cytotoxic drugs sensitize HT-29 colon cancer cells to TRAIL-induced cell death by enhancing FADD and procaspase-8 recruitment to the DISC, a novel mechanism whose efficacy could depend partly on Bcl-2 expression level.

Antineoplastic Agents↗
PubMed2003

Quinine as a multidrug resistance inhibitor: a phase 3 multicentric randomized study in adult de novo acute myelogenous leukemia.

Based on our previous demonstration that quinine could be used clinically to reverse P-glycoprotein-mediated resistance, we designed a multicenter, randomized trial aiming to determine whether quinine would improve the survival of adult patients (15-60 years old) with de novo acute myelogenous leukemia (AML). These patients randomly received (n = 213) or did not receive (n = 212) a 30 mg/kg/day continuous intravenous infusion of quinine in combination with induction chemotherapy combining idarubicine and cytarabine and, depending on bone marrow examination at day 20, an additional course of cytarabine and mitoxantrone. The mean steady-state quinine concentration was 7.8 mg/L and the mean multidrug resistance reversing activity of serum was 1.96. Complete remission (CR) was obtained in 344 patients (80.9%) without significant influence of quinine. Of the patients in complete remission, 82 were assigned to receive HLA-matched bone marrow transplants, whereas 262 were assigned to 2 courses of intensive consolidation chemotherapy, with or without quinine, depending on initial randomization. The 4-year actuarial overall survival (OS) of the 425 eligible patients was 42.0% +/- 2.5%, without significant influence of quinine. Of 160 patients who could be studied, 54 demonstrated rhodamine 123 efflux. In these patients, quinine significantly improved the CR rate from 12 of 25 (48.0%) to 24 of 29 (82.8%) (P =.01). However, there was no significant difference in OS. Neither mdr1 gene nor P-glycoprotein expression influenced the outcome. We conclude that quinine does not improve the survival of adult patients with de novo AML, even though it improves CR rate in a small subgroup of patients defined by rhodamine 123 efflux.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

The human caspase-2 gene: alternative promoters, pre-mRNA splicing and AUG usage direct isoform-specific expression.

Caspases have been shown to play important roles in apoptotic cell death, cytokine maturation and cell differentiation. However, the transcriptional regulation of the corresponding CASP genes remains poorly known. We describe a 5.1 kb fragment located upstream of the first translated exon in the human CASP-2 gene, which is known to encode caspase-2L and -2S protein isoforms. Transient transfection experiments, together with transcription start site mapping and transcript analysis, demonstrate that each caspase mRNA is initiated from separate promoter regions, and produced from alternative splicing events in these regions. The CASP-2L promoter is much stronger than the CASP-2S promoter, in good agreement with the respective transcript levels of the two caspases. In addition, several in-frame translational start sites can be identified for each isoform, one of which is common to both, present in the second common exon, and used efficiently. Surprisingly, the short isoform may also be initiated at a downstream AUG codon within the same exon. Thus, promoter strength, alternative transcriptional initiation and 5'-splicing events regulate the expression of the main caspase-2 isoforms that may be translated from alternative translation initiation codons.

5' Flanking Region↗
PubMed2003

Subcellular expression of c-IAP1 and c-IAP2 in colorectal cancers: relationships with clinicopathological features and prognosis.

The Inhibitor of Apoptosis Protein (IAP) family includes several critical cell death inhibitors, the expression of which could be involved in colorectal carcinogenesis. Among them, c-IAP1 and c-IAP2 expression has never been investigated in colorectal cancer. The present study was designed to determine whether expression of both IAPs was related to pathological parameters and survival in sporadic colon carcinomas. Analysis of five human colon cancer cell lines by both western blotting of cell fractions and immunocytochemistry showed that the two IAPs could be expressed both in the nucleus and in the cytoplasm. Immunohistochemical analysis of a series of 46 sporadic colorectal adenocarcinomas demonstrated that c-IAP1 expression was more frequent in the nucleus (85%), and that c-IAP2 was more often expressed in the cytoplasm (82%). A significant association was identified between a strong lymphoid infiltrate in the stroma and the nuclear expression of c-IAP2 (p = 0.02). No other relationship was observed between IAP expression and pathological features. After adjusting by age and stage, the relative risk of death was lower for cytoplasmic c-IAP1, cytoplasmic c-IAP2, and nuclear c-IAP2 expression. It was higher for nuclear c-IAP1 expression. These associations were not statistically significant, but this work underlines the importance of taking into account the subcellular location of the IAP family members in the evaluation of their prognostic significance.

Adult↗
PubMed2003

Mitochondria as a target for inducing death of malignant hematopoietic cells.

Mitochondria plays a central role in apoptotic cell death. The intermembrane space of mitochondria contains a number of soluble molecules whose release from the organelle to the cytosol or the nucleus induces cell death. Thus, molecules that directly trigger mitochondria membrane permeabilisation are efficient cytotoxic drugs. Mitochondria is one of the cellular targets for commonly used epipodophyllotoxins, adenine deoxynucleoside analogs and taxanes as well as recently developped agents such as the pentacyclic triterpene betulinic acid and the lymphotoxic agent FTY720. Most informations on anthracyclines point to the mitochondrial membrane as the main target of cardiotoxicity. Mitochondria is also a target for arsenite trioxide, an old cytotoxic agent recently used for treating acute promyelocytic leukemia, lonidamine, a dichlorinated derivative of indazole-3-carboxylic acid developped as a chemosensitizer, the retinoic acid receptor gamma activator CD437 and nitric oxide (NO). Recently, cytotoxic drugs have been specifically designed to directly affect the mitochondrial function. These include the positively charged alpha-helical peptides, which are attracted to and disrupt the negatively charged mitochondrial membrane, thus inducing mammalian cell apoptosis when targeted intracellularly. Various strategies have been proposed also to directly inhibit Bcl-2 and related anti-apoptotic proteins, including antisense oligonucleotides (e.g. Genasense, currently tested in phase III trials), small molecules that mimic the BH3 dimerization domain of these proteins and kinase inhibitors. Ligands of the mitochondrial benzodiazepine receptor such as the isoquinolone carboxamide derivative PK11195 also overcome the membrane-stabilizing effect of Bcl-2, whereas the adenosine nucleotide translocator (ANT) and the mitochondrial DNA are two other potential cellular targets for cytotoxic agents. Potentially, new compounds directly targeting the mitochondria may be useful in treating hematological malignancies. The challenge is now to selectively target these mitochondria permeabilizing agents to malignant cells. This review briefly summarizes the role of the mitochondria in cell death and describes these various strategies for targeting the mitochondria to induce apoptosis.

Adenosine Triphosphate↗
PubMed2003

HSP27 is a ubiquitin-binding protein involved in I-kappaBalpha proteasomal degradation.

HSP27 is an ATP-independent chaperone that confers protection against apoptosis through various mechanisms, including a direct interaction with cytochrome c. Here we show that HSP27 overexpression in various cell types enhances the degradation of ubiquitinated proteins by the 26S proteasome in response to stressful stimuli, such as etoposide or tumor necrosis factor alpha (TNF-alpha). We demonstrate that HSP27 binds to polyubiquitin chains and to the 26S proteasome in vitro and in vivo. The ubiquitin-proteasome pathway is involved in the activation of transcription factor NF-kappaB by degrading its main inhibitor, I-kappaBalpha. HSP27 overexpression increases NF-kappaB nuclear relocalization, DNA binding, and transcriptional activity induced by etoposide, TNF-alpha, and interleukin 1beta. HSP27 does not affect I-kappaBalpha phosphorylation but enhances the degradation of phosphorylated I-kappaBalpha by the proteasome. The interaction of HSP27 with the 26S proteasome is required to activate the proteasome and the degradation of phosphorylated I-kappaBalpha. A protein complex that includes HSP27, phosphorylated I-kappaBalpha, and the 26S proteasome is formed. Based on these observations, we propose that HSP27, under stress conditions, favors the degradation of ubiquitinated proteins, such as phosphorylated I-kappaBalpha. This novel function of HSP27 would account for its antiapoptotic properties through the enhancement of NF-kappaB activity.

Animals↗
PubMed2003

Bcl-2 proteins: targets and tools for chemosensitisation of tumor cells.

Proteins of the Bcl-2 family share one or several Bcl-2 homology (BH) regions and behave as pro- or anti-apoptotic proteins. Prosurvival members such as Bcl-2 and Bcl-X(L) are supposed to preserve mitochondrial outer membrane integrity, thus preventing the release of soluble apoptogenic molecules. Pro-apoptotic members include BH3-only proteins that act as sensors of cellular damage and initiate the death process and Bax-like proteins that act downstream of BH3-only proteins to permeabilise the mitochondrial outer membrane. Whether BH3-only proteins directly activate Bax-like proteins or prevent prosurvival members of the family from inhibiting Bax-like proteins or both remains a matter of controversy. Expression of these proteins is altered in various human tumours and this abnormal expression may contribute to oncogenesis and tumour cell resistance to anticancer drug-induced cell death. Based on these observations, prosurvival proteins are attractive intracellular targets for inducing tumour cell death or sensitising tumour cells to death induced by chemotherapeutic drugs. The use of 18-mer antisense oligonucleotides (G3139 or Genasense) targeting the first six codons of bcl-2 mRNA is currently developed in clinics with phase I studies demonstrating that thrombocytopenia may be the main dose-limiting side effect. This strategy, that efficiently decreases Bcl-2 protein expression in some tumour cells, is currently tested in phase II and phase III trials. Alternative approaches to achieve the functional knock-out of Bcl-2 include the use of either peptides mimicking the BH3 domain of Bcl-2-related proteins or more stable, non peptidic BH3 mimetics and the pharmacological modulation of the post-translational modifications of the protein.

Animals↗