Shooting at survivors: Bcl-2 family members as drug targets for cancer

Juin, Philippe; Geneste, Olivier; Raimbaud, Eric; Hickman, John A.

doi:10.1016/j.bbamcr.2003.10.010

Cited by 57 publications

(26 citation statements)

References 75 publications

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“…To further investigate the mechanism(s) by which NO donors sensitize A20 tumor cells to dendritic cellmediated killing, we analyzed the NO-treated tumor cells for alterations in their expression of proapoptotic and antiapoptotic proteins. One of the most well known protein families that regulate cell survival and apoptosis is the Bcl-2 family, in particular, Bcl-2 and Bcl-X L (25). The protective function of these proteins is, in great part, due to the formation of inactivating heterodimers with the proapoptotic protein Bax.…”

Section: No Sensitization Of Tumor Apoptosismentioning

confidence: 99%

Nitric Oxide Sensitizes Tumor Cells to Dendritic Cell–Mediated Apoptosis, Uptake, and Cross-Presentation

et al. 2005

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Dendritic cells are professional antigen-presenting cells associated with efficient antigen processing and presentation to T cells. However, recent evidence also suggests that dendritic cells may mediate direct tumoricidal functions. In this study, we investigated the mechanism by which murine dendritic cells mediate the apoptotic death of murine lymphoma cell lines, and whether dendritic cell effector function could be enhanced by preconditioning tumor cells with the protein phosphatase inhibitor nitric oxide (NO) by altering the balance of proapoptotic/antiapoptotic proteins in the treated cells. We observed that NO donor compound sensitized lymphomas to dendritic cell-mediated cytotoxicity in vitro. Both immature and spontaneously matured bone marrow-derived dendritic cells (SM-DC) were capable of inducing tumor cell apoptosis, with SM-DCs serving as comparatively better killers. Fas ligand (FasL)-Fas engagement proved important in this activity because elevated expression of membrane-bound FasL was detected on SM-DCs, and dendritic cells derived from FasL-deficient mice were less capable of killing NO-sensitized tumor cells than wild-type dendritic cells. As FasL-deficient dendritic cells were still capable of mediating a residual degree of tumor killing, this suggests that FasL-independent mechanisms of apoptosis are also involved in dendritic cell-mediated tumor killing. Because NO-treated tumor cells displayed a preferential loss of survivin protein expression via a proteasomedependent pathway, enhanced tumor sensitivity to dendritic cell-mediated killing may be associated with the accelerated turnover of this critical antiapoptotic gene product. Importantly, NO-treated tumor cells were also engulfed more readily than control tumor cells and this resulted in enhanced cross-presentation of tumor-associated antigens to specific T cells in vitro. (Cancer Res 2005; 65(18): 8461-70)

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Section: No Sensitization Of Tumor Apoptosismentioning

confidence: 99%

Nitric Oxide Sensitizes Tumor Cells to Dendritic Cell–Mediated Apoptosis, Uptake, and Cross-Presentation

et al. 2005

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“…More than a dozen compounds that may occupy the hydrophobic cleft of Bcl-2 (or regions close to it) and interfere with the binding properties of this survival protein have been reported (16)(17)(18). Of these, ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (HA14-1), a small organic compound of relatively simple chemical structure, was the first to be identified as a putative Bcl-2 inhibitor from in silico screens (19).…”

Section: Introductionmentioning

confidence: 99%

The Small Organic Compound HA14-1 Prevents Bcl-2 Interaction with Bax to Sensitize Malignant Glioma Cells to Induction of Cell Death

Manero¹,

Gautier²,

Gallenne³

et al. 2006

Cancer Research

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125

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A functional imbalance between proapoptotic Bax and antiapoptotic Bcl-2 is likely to participate in the resistance of cancer cells to therapy. We show here that ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (HA14-1), a small organic compound recently proposed to function as an inhibitor of Bcl-2, increases the sensitivity of human glioblastoma cells to radiotherapy and chemotherapy. This sensitizing effect is lost if Bcl-2 expression, but not Bcl-xL expression, is knocked down or if cells only express a mutant of Bax that does not interact with Bcl-2. This points to a specific Bcl-2 inhibitory function of HA14-1 and implies that it selectively involves hindrance of Bcl-2 binding to Bax, which HA14-1 inhibits in cell-free assays and in cells in receipt of an apoptotic stimulation. Moreover, HA14-1, in combination with a cytotoxic treatment, slows down the growth of glioblastoma in vivo. Thus, the inhibition of Bcl-2 achieved by HA14-1 might improve treatment outcome. (Cancer Res 2006; 66(5): 2757-64)

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“…Nr-13 belongs to a large family of apoptosis regulators sharing homology domains in the C-terminal moiety, including the conserved hydrophobic cleft, which is the binding site for BH3 peptides and related molecules (Juin et al, 2004). Thus, in order to maximize the chances of obtaining specific Nr-13 ligands, we focused on the N-terminal moiety of Nr-13 that shows poor homology with other Bcl-2-related proteins (Lalle et al, 2002).…”

Section: Resultsmentioning

confidence: 99%

“…Various approaches are being used to inactivate these proteins in tumor cells, for example, antisense oligonucleotides (Cotter et al, 1999), small synthetic inhibitors obtained from computer-based or functional screening of libraries (Wang et al, 2000;Jiang et al, 2003;Oltersdorf et al, 2005) or peptides mimicking the BH3 domain of apoptosis accelerators (Degterev et al, 2001;Walensky et al, 2004). Clinical trials are currently underway with a number of these potential new anticancer agents (Reed, 2003;Juin et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Modulation of Nr-13 antideath activity by peptide aptamers

Nouvion

Thibaut

et al. 2006

Oncogene

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Tumor cells are characterized by deregulated proliferation and resistance to proapoptotic stimuli. The Bcl-2 family of antiapoptotic proteins is overexpressed in a large number of chemoresistant tumors. Downregulation or inhibition of antiapoptotic proteins might result in the sensitization of cancer cells to chemotherapeutic agents. In the present study, we took advantage of the peptide aptamer strategy to target Nr-13, a Bcl-2 antiapoptotic protein involved in neoplastic transformation by the Rous sarcoma virus. We isolated peptide aptamers that behave as Nr-13 regulators, in vitro and in mammalian cells in culture. Some of these aptamers have potential proapoptotic activities. These data suggest that peptide aptamers targeting the Bcl-2 family of apoptosis inhibitors may be useful for the development of anticancer molecules.

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Shooting at survivors: Bcl-2 family members as drug targets for cancer

Cited by 57 publications

References 75 publications

Nitric Oxide Sensitizes Tumor Cells to Dendritic Cell–Mediated Apoptosis, Uptake, and Cross-Presentation

Nitric Oxide Sensitizes Tumor Cells to Dendritic Cell–Mediated Apoptosis, Uptake, and Cross-Presentation

The Small Organic Compound HA14-1 Prevents Bcl-2 Interaction with Bax to Sensitize Malignant Glioma Cells to Induction of Cell Death

Modulation of Nr-13 antideath activity by peptide aptamers

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