The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and Noxa activation independent of p53 status

Pérez-Galán, Patricia; Roué, Gaël; Villamor, Neus; Montserrat, Emili; Campo, Elı́as; Colomer, Dolors

doi:10.1182/blood-2005-05-2091

Cited by 431 publications

(427 citation statements)

References 48 publications

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“…Our data also suggest that OPM-1 cells have higher levels of Mcl-1 than Bcl-2 and are relatively less sensitive to treatment with ABT-737 (Figure 1 and 3c). These observations suggest that combining ABT-737 Adams, 2005), and a recent study showed that proteasome inhibitor bortezomib/Velcade induces Noxa expression in MM cells (Qin et al, 2005;Perez-Galan et al, 2006). We therefore examined whether combining ABT-737 with bortezomib trigger additive anti-MM activity.…”

Section: Bcl-2 Inhibition As Therapy In Multiple Myeloma D Chauhan Et Almentioning

confidence: 96%

A novel Bcl-2/Bcl-XL/Bcl-w inhibitor ABT-737 as therapy in multiple myeloma

et al. 2006

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Bcl-2 or Bcl-X L confers resistance to chemotherapy in multiple myeloma (MM). Here we characterized the effects of ABT-737, a potent small-molecule inhibitor of antiapoptotic proteins Bcl-2, Bcl-X L and Bcl-w with markedly higher affinity than previously reported compounds, on human MM cells. ABT-737 induces apoptosis in MM cells, including those resistant to conventional therapy. Examination of purified patient MM cells demonstrated similar results, without significant toxicity against normal peripheral blood mononuclear cells and MM bone marrow stromal cells. Importantly, ABT-737 decreases the viability of bortezomib-, dexamethasone-(Dex) and thalidomide-refractory patient MM cells. Additionally, ABT-737 abrogates MM cell growth triggered by interleukin-6 or insulin-like growth factor-1. Mechanistic studies show that ABT-737-induced apoptosis is associated with activation of caspase-8, caspase-9 and caspase-3, followed by poly(ADP-ribose) polymerase cleavage. Combining ABT-737 with proteasome inhibitor bortezomib, melphalan or dexamethasone induces additive anti-MM activity. Taken together, our study provides the rationale for clinical protocols evaluating ABT-737, alone and together with botezomib, mephalan or dexamethasone, to enhance MM cell killing, overcome drug resistance conferred by Bcl-2 and improve patient outcome in MM.

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Section: Bcl-2 Inhibition As Therapy In Multiple Myeloma D Chauhan Et Almentioning

confidence: 96%

A novel Bcl-2/Bcl-XL/Bcl-w inhibitor ABT-737 as therapy in multiple myeloma

et al. 2006

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“…95 Moreover, proteasomes degrade several proteins involved in cell-cycle control, 96 again suggesting that the benefical effects of bortezomib could involve the accumulation of proteins that are not related to NF-kB. According to one study, bortezomib responses could be linked to the upregulation of the proapoptotic Bcl-2 protein family member NOXA 93 (Figure 4).…”

Section: Therapeutic Strategies Targeting Nf-jbmentioning

confidence: 99%

“…Clinical trials are currently undertaken to evaluate its therapeutic potential in other hematologic malignancies. Objective responses have been observed for non-Hodgkin's lymphomas (including mantle cell lymphoma) and AML [92][93][94] The recent observation that bortezomib induces apoptosis ex vivo in purified MDS hematopoietic stem cells suggests that bortezomib may be indicated in this disease as well as for AML patients 10 ( Figure 4). Of note, however, is that it is not clear whether the therapeutic effects of bortezomib are entirely due to inhibition of NF-kB or whether bortezomib may act on other relevant targets.…”

Section: Therapeutic Strategies Targeting Nf-jbmentioning

confidence: 99%

Targeting NF-κB in hematologic malignancies

et al. 2006

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The transcription factor nuclear factor kappa B (NF-jB) can intervene in oncogenesis by virtue of its capacity to regulate the expression of a plethora of genes that modulate apoptosis, and cell survival as well as proliferation, inflammation, tumor metastasis and angiogenesis. Different reports demonstrate the intrinsic activation of NF-jB in lymphoid and myeloid malignancies, including preneoplastic conditions such as myelodysplastic syndromes, underscoring its implication in malignant transformation. Targeting intrinsic NF-jB activation, as well as its upstream and downstream regulators, may hence constitute an additional approach to the oncologist's armamentarium. Several small inhibitors of the NF-jB-activatory kinase IjB kinase, of the proteaseome, or of the DNA binding of NF-jB subunits are under intensive investigation. Currently used cytotoxic agents can induce NF-jB activation as an unwarranted side effect, which confers apoptosis suppression and hence resistance to these drugs. Thus, NF-jB inhibitory molecules may be clinically useful, either as single therapeutic agents or in combination with classical chemotherapeutic agents, for the treatment of hematological malignancies.

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“…6 Genetic and functional studies in melanoma and other cancers have identified the proapoptotic protein NOXA as an early target of bortezomib. [5][6][7][8]10,11 The specific contribution of NOXA to cell death may be context dependent, 12 but a main role of this protein is to neutralize the antiapoptotic factor Mcl-1. 13,14 Intriguingly, while a 5-to 20-fold accumulation of NOXA in melanoma cells can be visualized as early as 6 h posttreatment with bortezomib, caspase activation may not be detected until 12-48 h later.…”

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confidence: 99%

Therapeutic window for melanoma treatment provided by selective effects of the proteasome on Bcl-2 proteins

et al. 2007

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Melanoma cells depend on sustained proteasomal function for survival. However, bortezomib, the first proteasome inhibitor in clinical use, is not sufficient to improve the poor prognosis of metastatic melanoma patients. Since the proteasome is also expressed in all normal cell compartments, it is unclear how to enhance the efficacy of bortezomib without exacerbating secondary toxicities. Here, we present pharmacological and genetic analyses of mechanisms of resistance to proteasome inhibition. We focused on Bcl-2, Bcl-x L and Mcl-1 as main antiapoptotic factors associated with melanoma progression. Despite an efficient blockage of the proteasome, bortezomib could not counteract the intrinsically high levels of Bcl-2 and Bcl-x L in melanoma cells. Moreover, Mcl-1 was only downregulated at late time points after treatment. Based on these results, a combination treatment including (À)-gossypol, an inhibitor of Mcl-1/Bcl-2/Bcl-x L , was designed and proven effective in vivo. Using a specific RNA interference approach, the survival of bortezomib-treated melanoma cells was found to rely primarily on Mcl-1, and to a lesser extent on Bcl-x L (but not on Bcl-2). Importantly, neither Mcl-1 nor Bcl-x L inactivation affected the viability of normal melanocytes. This hierarchical requirement of Bcl-2 family members for the maintenance of normal and malignant cells offers a therapeutic window to overcome melanoma chemoresistance in a tumor cell-selective manner.

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The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and Noxa activation independent of p53 status

Cited by 431 publications

References 48 publications

A novel Bcl-2/Bcl-XL/Bcl-w inhibitor ABT-737 as therapy in multiple myeloma

A novel Bcl-2/Bcl-XL/Bcl-w inhibitor ABT-737 as therapy in multiple myeloma

Targeting NF-κB in hematologic malignancies

Therapeutic window for melanoma treatment provided by selective effects of the proteasome on Bcl-2 proteins

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