Proteasome Inhibitors in Cancer Therapy

Orłowski, Robert Z.

doi:10.1385/1-59259-895-1:339

Cited by 13 publications

(17 citation statements)

References 83 publications

(112 reference statements)

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“…Cancer Res 2007; 67: (24 is approved for treatment of multiple myeloma patients who have relapses from prior therapies (29). Treatment of MG132 at 1 Amol/L or of bortezomib at 10 nmol/L induced significant cell death in H929, U266, RPMI8226, and IM9 cells (data not shown), as previously reported (30).…”

Section: Cancer Researchsupporting

confidence: 76%

Induction of Apoptosis in Plasma Cells by B Lymphocyte–Induced Maturation Protein-1 Knockdown

et al. 2007

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B lymphocyte-induced maturation protein-1 (Blimp-1) is a transcriptional repressor that plays an important role during plasmacytic differentiation and is expressed in normal and transformed plasma cells. We here investigated the importance of continuous Blimp-1 expression. We found that knockdown of Blimp-1 expression by lentiviral vector-delivered short hairpin RNA causes apoptosis in multiple myeloma cell lines and plasmacytoma cells, indicating that continued expression of Blimp-1 is required for cell survival. We examined the mechanism underlying Blimp-1 knockdown-mediated apoptosis and found that the Blimp-1 knockdown neither reversed the phenotypic markers of plasma cells nor caused cell cycle arrest. Instead, our results show that knockdown of Blimp-1 induced the proapoptotic protein Bim, reduced the antiapoptotic protein Mcl-1, and activated caspase-9 and caspase-3. We further link apoptosis in transformed plasma cells mediated by proteasome inhibitors, the effective therapeutic agent for multiple myeloma patients, with reduced expression of Blimp-1. Lastly, we show that Blimp-1-dependent cell survival may act downstream of IFN regulatory factor 4 (IRF4) because IRF4 knockdown leads to down-regulation of Blimp-1 and apoptosis in multiple myeloma cells and plasmacytoma cells. Together, our data suggest that Blimp-1 ensures the survival of transformed plasma cells.

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Section: Cancer Researchsupporting

confidence: 76%

Induction of Apoptosis in Plasma Cells by B Lymphocyte–Induced Maturation Protein-1 Knockdown

et al. 2007

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“…The proteasome inhibitor Velcade  (Bortezomib, PS-341; Millennium Pharmaceuticals) is currently approved for the treatment of multiple myeloma and is in development for other indications. 30 By blocking ubiquitin-mediated protein degradation, Bortezomib is predicted to interfere with, among others, survival mechanisms associated with nuclear factor (NF)-κB pathways. It has also been shown to cause elevation of BH3-only NOXA, 31,32 a preferred binding partner for MCL-1.…”

Section: Rational Combination Treatmentsmentioning

confidence: 99%

Modulating the Bcl-2 Family of Apoptosis Suppressors for Potential Therapeutic Benefit in Cancer

Shore¹,

Viallet²

2005

Hematology

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Members of the BCL-2 family of proteins regulate and execute many cell intrinsic apoptosis pathways, including those arising from dysregulated expression of cellular oncogenes. Since pro-survival members of the family are often strongly elevated in diverse cancers, with the potential to confer resistance to both endogenous cell death stimuli and many cancer treatments, there has been intense interest to develop strategies to therapeutically modulate their activity. Although encouraging genetic and pharmacological preclinical proof of concept has been obtained, the challenge for clinical development will be to devise strategies that address the fact that multiple pro-survival members are typically up-regulated in a given cancer and the family operates primarily through protein-protein interactions. Moreover, since several current therapies themselves are known to stimulate the levels of one or more family members, there will be additional challenges (and opportunities) in exploiting this target in the clinic. In this review, we describe the rationale for targeting the BCL-2 family of apoptosis suppressors in cancer and the progress that has been made in modulating the family by small molecule antagonists.

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“…Thus, agents that interfere with the ubiquitin-proteasome pathway will induce Hsp70 expression. Germane to this point, it is worth noting that a proteasome inhibitor, known as Bortezomib (Velcade®, or "PS-341"), has been FDA-approved for the treatment of multiple myeloma [165,166], and we suggest that Hsc70 inhibitors could potentiate the effects of this compound.…”

Section: B Inducers Of Hsp70 Expressionmentioning

confidence: 97%

Hsp70 Molecular Chaperones: Emerging Roles in Human Disease and Identification of Small Molecule Modulators

Brodsky

Chiosis²

2006

CTMC

189

196

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Molecular chaperones are best known for their ability to aid in the solubilization of mis-folded proteins, and as a result play essential roles in protein folding, degradation, and transport. However, many molecular chaperones also play essential roles in signal transduction cascades. For example, Hsp70 molecular chaperones are a highly conserved, abundant class of chaperones that are found in every species and in nearly every cellular compartment in eukaryotes. In addition to their well-established roles in facilitating protein folding and in the targeting of proteins to organelles and to proteolytic machines, Hsp70s are anti-apoptotic and inhibition of Hsp70 function in some cases is sufficient to induce tumor cell death. Hsp70 function is also vital for the replication of viruses. Based on these data, small molecule Hsp70 modulators might, in principle, be used for the treatment of specific cancers, infections, and protein conformational diseases. In this review, we summarize the structural and functional characteristics of Hsp70 chaperones, and then discuss their roles in cellular physiology. Finally, we will review the recent discovery of small molecules that alter Hsp70 expression and function.

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Proteasome Inhibitors in Cancer Therapy

Cited by 13 publications

References 83 publications

Induction of Apoptosis in Plasma Cells by B Lymphocyte–Induced Maturation Protein-1 Knockdown

Induction of Apoptosis in Plasma Cells by B Lymphocyte–Induced Maturation Protein-1 Knockdown

Modulating the Bcl-2 Family of Apoptosis Suppressors for Potential Therapeutic Benefit in Cancer

Hsp70 Molecular Chaperones: Emerging Roles in Human Disease and Identification of Small Molecule Modulators

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