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Proteasome inhibition and its therapeutic potential in multiple myeloma.

Chari A, Mazumder A, Jagannath S - Biologics (2010)

Bottom Line: Due to an unmet clinical need for treatment, the first in class proteasome inhibitor, bortezomib, moved from drug discovery to FDA approval in multiple myeloma in an unprecedented eight years.In the wake of this rapid approval arose a large number of questions about its mechanism of action and toxicity as well as its ultimate role in the treatment of this disease.We conclude with our current understanding of the mechanism of action of this agent and a discussion of the novel proteasome inhibitors under development, as it will be progress in these areas that will ultimately determine the true potential of proteasome inhibition in myeloma.

View Article: PubMed Central - PubMed

Affiliation: Mount Sinai School of Medicine, New York, NY, USA.

ABSTRACT
Due to an unmet clinical need for treatment, the first in class proteasome inhibitor, bortezomib, moved from drug discovery to FDA approval in multiple myeloma in an unprecedented eight years. In the wake of this rapid approval arose a large number of questions about its mechanism of action and toxicity as well as its ultimate role in the treatment of this disease. In this article, we briefly review the preclinical and clinical development of the drug as the underpinning for a systematic review of the large number of clinical trials that are beginning to shed some light on the full therapeutic potential of bortezomib in myeloma. We conclude with our current understanding of the mechanism of action of this agent and a discussion of the novel proteasome inhibitors under development, as it will be progress in these areas that will ultimately determine the true potential of proteasome inhibition in myeloma.

No MeSH data available.


Related in: MedlinePlus

NF-κB activation pathway. The inhibitor protein I-κB, when bound to NF-κB in the cytoplasm, renders NF-κB inactive. A variety of cellular stimuli result in the phosphorylation and ubiquitination of I-κB, thereby targeting it for proteasome mediated degradation. Bortezomib, by inhibiting the proteasome, results in increased I-κB inhibition of NF-κB, thus resulting in inhibition of tumor growth. Reproduced with permission from Adams J. Potential for proteasome inhibition in the treatment of cancer. Drug Discov Today. 2003;8(7):307–315.3 Copyright © 2003 Elsevier.
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f7-btt-4-273: NF-κB activation pathway. The inhibitor protein I-κB, when bound to NF-κB in the cytoplasm, renders NF-κB inactive. A variety of cellular stimuli result in the phosphorylation and ubiquitination of I-κB, thereby targeting it for proteasome mediated degradation. Bortezomib, by inhibiting the proteasome, results in increased I-κB inhibition of NF-κB, thus resulting in inhibition of tumor growth. Reproduced with permission from Adams J. Potential for proteasome inhibition in the treatment of cancer. Drug Discov Today. 2003;8(7):307–315.3 Copyright © 2003 Elsevier.

Mentions: Initial focus was on the impact of bortezomib on NF-κB, which promotes tumor cell survival and proliferation. The inhibitor protein I-κB binds NF-κB in the cytoplasm, thereby rendering NF-κB inactive. A variety of cytokines and other cellular stimuli result in the phosphorylation and ubiquitination of I-κB by E3 ligase, thus targeting it for proteasome mediated degradation (Figure 7).2


Proteasome inhibition and its therapeutic potential in multiple myeloma.

Chari A, Mazumder A, Jagannath S - Biologics (2010)

NF-κB activation pathway. The inhibitor protein I-κB, when bound to NF-κB in the cytoplasm, renders NF-κB inactive. A variety of cellular stimuli result in the phosphorylation and ubiquitination of I-κB, thereby targeting it for proteasome mediated degradation. Bortezomib, by inhibiting the proteasome, results in increased I-κB inhibition of NF-κB, thus resulting in inhibition of tumor growth. Reproduced with permission from Adams J. Potential for proteasome inhibition in the treatment of cancer. Drug Discov Today. 2003;8(7):307–315.3 Copyright © 2003 Elsevier.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2990320&req=5

f7-btt-4-273: NF-κB activation pathway. The inhibitor protein I-κB, when bound to NF-κB in the cytoplasm, renders NF-κB inactive. A variety of cellular stimuli result in the phosphorylation and ubiquitination of I-κB, thereby targeting it for proteasome mediated degradation. Bortezomib, by inhibiting the proteasome, results in increased I-κB inhibition of NF-κB, thus resulting in inhibition of tumor growth. Reproduced with permission from Adams J. Potential for proteasome inhibition in the treatment of cancer. Drug Discov Today. 2003;8(7):307–315.3 Copyright © 2003 Elsevier.
Mentions: Initial focus was on the impact of bortezomib on NF-κB, which promotes tumor cell survival and proliferation. The inhibitor protein I-κB binds NF-κB in the cytoplasm, thereby rendering NF-κB inactive. A variety of cytokines and other cellular stimuli result in the phosphorylation and ubiquitination of I-κB by E3 ligase, thus targeting it for proteasome mediated degradation (Figure 7).2

Bottom Line: Due to an unmet clinical need for treatment, the first in class proteasome inhibitor, bortezomib, moved from drug discovery to FDA approval in multiple myeloma in an unprecedented eight years.In the wake of this rapid approval arose a large number of questions about its mechanism of action and toxicity as well as its ultimate role in the treatment of this disease.We conclude with our current understanding of the mechanism of action of this agent and a discussion of the novel proteasome inhibitors under development, as it will be progress in these areas that will ultimately determine the true potential of proteasome inhibition in myeloma.

View Article: PubMed Central - PubMed

Affiliation: Mount Sinai School of Medicine, New York, NY, USA.

ABSTRACT
Due to an unmet clinical need for treatment, the first in class proteasome inhibitor, bortezomib, moved from drug discovery to FDA approval in multiple myeloma in an unprecedented eight years. In the wake of this rapid approval arose a large number of questions about its mechanism of action and toxicity as well as its ultimate role in the treatment of this disease. In this article, we briefly review the preclinical and clinical development of the drug as the underpinning for a systematic review of the large number of clinical trials that are beginning to shed some light on the full therapeutic potential of bortezomib in myeloma. We conclude with our current understanding of the mechanism of action of this agent and a discussion of the novel proteasome inhibitors under development, as it will be progress in these areas that will ultimately determine the true potential of proteasome inhibition in myeloma.

No MeSH data available.


Related in: MedlinePlus