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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

The unfolded protein response. If misfolded proteins accumulate in endoplastic reticulum, the sensing mechanism IRE1α activates the transcription factor XBP-1 via IRE 1 kinase. XBP-1, in turn, activates the unfolded protein response (UPR) and results in apoptosis.
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f9-btt-4-273: The unfolded protein response. If misfolded proteins accumulate in endoplastic reticulum, the sensing mechanism IRE1α activates the transcription factor XBP-1 via IRE 1 kinase. XBP-1, in turn, activates the unfolded protein response (UPR) and results in apoptosis.

Mentions: Once the UPR is activated, the unfolded proteins are refolded by upregulation of the chaperone molecules or destroyed through cytosolic 26S proteasomes; otherwise, accumulation of unfolded protein results in apoptosis of the cell (Figure 9). Proteasome inhibition triggers apoptosis by interfering with the UPR pathway, both at the sensing level as well as by preventing destruction of misfolded protein.79


Proteasome inhibition and its therapeutic potential in multiple myeloma.

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

The unfolded protein response. If misfolded proteins accumulate in endoplastic reticulum, the sensing mechanism IRE1α activates the transcription factor XBP-1 via IRE 1 kinase. XBP-1, in turn, activates the unfolded protein response (UPR) and results in apoptosis.
© Copyright Policy
Related In: Results  -  Collection

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

f9-btt-4-273: The unfolded protein response. If misfolded proteins accumulate in endoplastic reticulum, the sensing mechanism IRE1α activates the transcription factor XBP-1 via IRE 1 kinase. XBP-1, in turn, activates the unfolded protein response (UPR) and results in apoptosis.
Mentions: Once the UPR is activated, the unfolded proteins are refolded by upregulation of the chaperone molecules or destroyed through cytosolic 26S proteasomes; otherwise, accumulation of unfolded protein results in apoptosis of the cell (Figure 9). Proteasome inhibition triggers apoptosis by interfering with the UPR pathway, both at the sensing level as well as by preventing destruction of misfolded protein.79

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