The therapeutic potential of the proteasome in leukaemia

McCloskey, Scott; McMullin, Mary Frances; Walker, Brian; Irvine, Alexandra

doi:10.1002/hon.848

Cited by 15 publications

(15 citation statements)

References 99 publications

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“…CD81N1/CD82N1 causes ER-stress and autophagic death in MM V Zismanov et al of its action modes (McCloskey et al, 2008). Our findings suggest the possibility that ER-stress may be achieved by increased protein synthesis and interestingly, this may be the path of least resistance, because it is in sync with built-in MM characteristics, hence the 'Achilles' heel' of these cells.…”

Section: Discussionmentioning

confidence: 63%

Tetraspanin-induced death of myeloma cell lines is autophagic and involves increased UPR signalling

et al. 2009

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BACKGROUND: Multiple myeloma (MM) therapy is hindered by the interaction of the heterogeneous malignant plasma cells with their microenvironment and evolving drug resistance. We have previously shown that the membranal tetraspanins, CD81 and CD82, are under-expressed in MM cells and that their reintroduction causes massive non-apoptotic death. In this study, we aimed to characterise the tetraspanin-induced MM death. METHODS: Multiple myeloma cell lines were transiently transfected with eGFP -CD81N1/CD82N1 fusion proteins and assessed for death mode by flow cytometry (propidium iodide, ZVAD-fmk, 3MA), activation of unfolded protein response (UPR), and autophagy (immunoblot, RT -PCR). RESULTS: Cell death induced by CD81N1 and CD82N1 in MM cell lines was autophagic and involved endoplasmic reticulum (ER)-stress manifested by activation of UPR pathways, PERK (protein kinase-like ER kinase) and IRE1 (inositol-requiring 1). We also established the relative X-box binding protein 1 baseline expression levels in a panel of MM cell lines and their general dependence on autophagy for survival. Timeline of UPR cascades and cell fate supported our results. INTERPRETATION: This is the first publication implicating tetraspanins in UPR signalling pathways, autophagy, and autophagic death. Integration of our findings with published data highlights the unifying dependence of MM cells on ER -Golgi homoeostasis, and underscores the potential of tetraspanin complexes and ER-stress as leverage for MM therapy.

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Section: Discussionmentioning

confidence: 63%

Tetraspanin-induced death of myeloma cell lines is autophagic and involves increased UPR signalling

et al. 2009

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“…Both RAW 264.7 macrophage cells and YAMC cells were treated with Lp-CM at the same dose and for the same time period used previously to inhibit NF- κ B activation and proteasome activity. In contrast to the proteasome inhibitor bortezomib (Velcade®), which is used clinically for the treatment of human hematologic malignancies,35 no toxicity was observed with Lp-CM after 4 hours of exposure (Fig. 9A).…”

Section: Resultsmentioning

confidence: 99%

Bacteria-free solution derived from lactobacillus plantarum inhibits multiple NF-kappaB pathways and inhibits proteasome function

Petrof

Claud

Sun

et al. 2009

Inflammatory Bowel Diseases

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Background-Bacteria play a role in inflammatory bowel disease and other forms of intestinal inflammation. Although much attention has focused on the search for a pathogen or inciting inflammatory bacteria, another possibility is a lack of beneficial bacteria that normally confer antiinflammatory properties in the gut. The purpose of this study was to determine whether normal commensal bacteria could inhibit inflammatory pathways important in intestinal inflammation.

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“…Results of studies in this field stongly suggest that proteasome inhibition should be considered in antileukemic therapies [134,135]. Moreover, a new generation of irreversible proteasome inhibitors (salinosporamide A and carfilzomib) that in preclinical studies at least partially overcome bortezomib resistance in vitro have been developed.…”

Section: Discussionmentioning

confidence: 98%

Antiproliferative and Proapoptotic Effects of Proteasome Inhibitors and their Combination with Histone Deacetylase Inhibitors on Leukemia Cells

Fuchs¹,

Provazníková²,

Marinov³

et al. 2009

CHDDT

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New chemotherapeutic agents are still required to further optimise treatment of leukemia patients. Proteasome inhibition by bortezomib, PR-171 (carfilzomib) and NPI-0052 (salinosporamide A) has been successfully used for the treatment of multiple myeloma and mantle cell lymphoma and is considered also as novel treatment strategy in leukemia. Combination of proteasome inhibitors bortezomib and NPI-0052 induces synergistic anti-multiple myeloma activity both in vitro using multiple myeloma cells and in vivo in a human plasmacytoma xenograft mouse model. Cell death resulting from proteasome inhibition requires caspase activation and increased levels of reactive oxygen species. While bortezomib induces several caspases, NPI-0052 activates predominantly caspase-8-dependent pathway. We studied the effect of bortezomib (10 nM) on DNA synthesis and apoptosis in human acute myeloid cell lines KASUMI-1, ML-1, ML-2 and CTV-1 cells. Bortezomib was potent inhibitor of DNA synthesis in all four types of leukemia cells and induced apoptosis in KASUMI-1, ML-2 and CTV-1 cells but not in ML-1 cells. Other research groups showed that histone deacetylase inhibitors (valproic acid or benzamide derivative MS-275) in combination with NPI-0052 or PR-171 induced greater levels of acute leukemia cell death than in combination with bortezomib. Proteasome inhibition as monotherapy and its combination with many conventional therapies as novel treatment strategies in leukemia are promising. Malignant cells are more sensitive to this treatment than normal hematopoietic cells.

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The therapeutic potential of the proteasome in leukaemia

Cited by 15 publications

References 99 publications

Tetraspanin-induced death of myeloma cell lines is autophagic and involves increased UPR signalling

Tetraspanin-induced death of myeloma cell lines is autophagic and involves increased UPR signalling

Bacteria-free solution derived from lactobacillus plantarum inhibits multiple NF-kappaB pathways and inhibits proteasome function

Antiproliferative and Proapoptotic Effects of Proteasome Inhibitors and their Combination with Histone Deacetylase Inhibitors on Leukemia Cells

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