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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

Alteration in levels of Mcl-1 and NOXA results in apoptosis. Proteasome inhibiton increases levels of the proapoptoic factor NOXA, which then can override the concurrent increase in the anti-apoptic factor Mcl-1, thereby inducing the activation of caspases, and resulting in apoptosis.
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f8-btt-4-273: Alteration in levels of Mcl-1 and NOXA results in apoptosis. Proteasome inhibiton increases levels of the proapoptoic factor NOXA, which then can override the concurrent increase in the anti-apoptic factor Mcl-1, thereby inducing the activation of caspases, and resulting in apoptosis.

Mentions: When myeloma cell lines are exposed to bortezomib, the proapoptotic factor NOXA is induced in a concentration dependent manner accompanied by the activation of caspases. NOXA is also induced by p53 and other transcriptional factors such as hypoxia-inducible factor 1 (HIF-1) and E2F-1, consistent with its involvement in the response to many types of cellular stress. Human NOXA contains one BH3 (Bcl-2 homology 3) domain, which has a high affinity for the antiapoptotic factor Mcl-1. Because Mcl-1 is a target for ubiquitination, proteasome inhibition increases levels of Mcl-1. The induction of NOXA is therefore essential to override high Mcl-1 levels and allow for the activation of the apoptotic machinery in response to bortezomib.72 Also, NOXA’s interaction with anti-apoptotic members of the Bcl-2 family causes release of cytochrome c into the cytosol, leading to the activation of caspases and induction of apoptosis (Figure 8).73


Proteasome inhibition and its therapeutic potential in multiple myeloma.

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

Alteration in levels of Mcl-1 and NOXA results in apoptosis. Proteasome inhibiton increases levels of the proapoptoic factor NOXA, which then can override the concurrent increase in the anti-apoptic factor Mcl-1, thereby inducing the activation of caspases, and resulting in apoptosis.
© Copyright Policy
Related In: Results  -  Collection

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

f8-btt-4-273: Alteration in levels of Mcl-1 and NOXA results in apoptosis. Proteasome inhibiton increases levels of the proapoptoic factor NOXA, which then can override the concurrent increase in the anti-apoptic factor Mcl-1, thereby inducing the activation of caspases, and resulting in apoptosis.
Mentions: When myeloma cell lines are exposed to bortezomib, the proapoptotic factor NOXA is induced in a concentration dependent manner accompanied by the activation of caspases. NOXA is also induced by p53 and other transcriptional factors such as hypoxia-inducible factor 1 (HIF-1) and E2F-1, consistent with its involvement in the response to many types of cellular stress. Human NOXA contains one BH3 (Bcl-2 homology 3) domain, which has a high affinity for the antiapoptotic factor Mcl-1. Because Mcl-1 is a target for ubiquitination, proteasome inhibition increases levels of Mcl-1. The induction of NOXA is therefore essential to override high Mcl-1 levels and allow for the activation of the apoptotic machinery in response to bortezomib.72 Also, NOXA’s interaction with anti-apoptotic members of the Bcl-2 family causes release of cytochrome c into the cytosol, leading to the activation of caspases and induction of apoptosis (Figure 8).73

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