Combined autophagy and proteasome inhibition

Vogl, Dan T.; Stadtmauer, Edward A.; Tan, Kay See; Heitjan, Daniel F.; Davis, Lisa E.; Pontiggia, Laura; Rangwala, Reshma; Piao, Shengfu; Chang, Yulin V.; Scott, Emma C.; Paul, Thomas M.; Nichols, Charles W.; Porter, David; Kaplan, Janeen; Mallon, G.; Bradner, James E.; Amaravadi, Ravi K.

doi:10.4161/auto.29264

Cited by 323 publications

(157 citation statements)

References 42 publications

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“…Earlier reports linked bortezomib resistance to the induction of autophagy; this notion led to an ongoing clinical trial of combined bortezomib and an autophagy inhibitor hydroxychloroquine in MM patients. 43 Whether RA190-induced autophagy results in the development of drug resistance remains to be determined, but our findings indicate the therapeutic potential of combining inhibitors of Rpn13 and autophagy.…”

Section: Resultsmentioning

confidence: 78%

Targeting proteasome ubiquitin receptor Rpn13 in multiple myeloma

Song

Ray

et al. 2016

Leukemia

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Proteasome inhibitor bortezomib is an effective therapy for relapsed and newly diagnosed multiple myeloma (MM); however, dose-limiting toxicities and the development of resistance can limit its long-term utility. Recent research has focused on targeting ubiquitin receptors upstream of 20S proteasome, with the aim of generating less toxic therapies. Here we show that 19S proteasome-associated ubiquitin receptor Rpn13 is more highly expressed in MM cells than in normal plasma cells. Rpn13-siRNA (small interfering RNA) decreases MM cell viability. A novel agent RA190 targets Rpn13 and inhibits proteasome function, without blocking the proteasome activity or the 19S deubiquitylating activity. CRISPR/Cas9 Rpn13-knockout demonstrates that RA190-induced activity is dependent on Rpn13. RA190 decreases viability in MM cell lines and patient MM cells, inhibits proliferation of MM cells even in the presence of bone marrow stroma and overcomes bortezomib resistance. Anti-MM activity of RA190 is associated with induction of caspase-dependent apoptosis and unfolded protein response-related apoptosis. MM xenograft model studies show that RA190 is well tolerated, inhibits tumor growth and prolongs survival. Combining RA190 with bortezomib, lenalidomide or pomalidomide induces synergistic anti-MM activity. Our preclinical data validates targeting Rpn13 to overcome bortezomib resistance, and provides the framework for clinical evaluation of Rpn13 inhibitors, alone or in combination, to improve patient outcome in MM.

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Section: Resultsmentioning

confidence: 78%

Targeting proteasome ubiquitin receptor Rpn13 in multiple myeloma

Song

Ray

et al. 2016

Leukemia

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“…We then prepared a number of analogs to evaluate the effect of the N-carboxyalkylacyl chain length (from C3 to C8) and including ether and branched alkyl substitution in the chain. We found that peptides with N-capping chains HO 2 C(CH 2 ) n CO-NH with n = 2, 3, 4, 5 or 6 ( Table 1; compounds 3, 14,15,16,17) were substrates for ATG4B with n = 5 being optimal. The introduction of an ether (Table 1; compound 18) or small alkyl branched chains (Table 1; compounds 11, 12) was less well accepted.…”

Section: Design and Synthesis Of Atg4b Fluorogenic Peptide Substratesmentioning

confidence: 97%

“…Recent clinical evidence suggest that existing lysosomotropic agents such as HCQ may not effectively inhibit autophagy in vivo at maximum tolerable doses. 7,[15][16][17][18] On-going studies with more potent lysosomal autophagy inhibitors such as Lys05 hold some promise. 14 The process of autophagy begins when double-walled isolation membranes within the cytosol are induced to form vesicles, termed autophagosomes, effectively engulfing the offending cellular http://dx.doi.org/10.1016/j.bmc.2015.04.064 0968-0896/Ó 2015 Elsevier Ltd. All rights reserved.…”

Section: Introductionmentioning

confidence: 99%

Development of fluorescent peptide substrates and assays for the key autophagy-initiating cysteine protease enzyme, ATG4B

Vezenkov

Honson

Kumar

et al. 2015

Bioorganic & Medicinal Chemistry

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“…Furthermore, unfortunately, single proteasome inhibitor treatment has been proven unsatisfactory for solid tumors in clinical trials 5, 6. A recent clinical trial suggested that the anticancer effect of Bor is enhanced when it is combined with an autophagy inhibitor 7. To date, autophagy inhibitors including hydroxychloroquine (HCQ) and chloroquine (CQ) have been clinically viable.…”

Section: Introductionmentioning

confidence: 99%

Titania‐Coated Gold Nano‐Bipyramids for Blocking Autophagy Flux and Sensitizing Cancer Cells to Proteasome Inhibitor‐Induced Death

et al. 2017

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Targeting protein degradation is recognized as a valid approach to cancer therapy. The ubiquitin–proteasome system (UPS) and the autophagy–lysosome pathway are two major pathways for intracellular protein degradation. Proteasome inhibitors such as bortezomib are clinically approved for treating malignancies, but to date, they are still unsatisfactory for cancer therapy. This study identifies titania‐coated gold nano‐bipyramid (NBP/TiO2) nanostructures as an autophagic flux inhibitor, as the smallest NBP/TiO2 nanostructures induce significant autophagosome accumulation in human glioblastoma U‐87 MG cells via blocking the autophagosome–lysosome fusion process and inhibiting lysosomal degradation. Further study indicates that NBP/TiO2 nanostructures reduce the intracellular level of mature cathepsin B and directly inhibit the proteolytic activity of cathepsin B, thereby further inhibiting trypsin‐like proteolytic activity, which is a potential cotarget for UPS inhibition. NBP/TiO2 nanostructures interact synergistically with bortezomib to suppress the viability of U‐87 MG cells, as the combined treatment synergistically induces the intracellular accumulation of ubiquitinated protein and endoplasmic reticulum stress. In addition, photothermal therapy further synergistically reduces the cell viability. In summary, this study suggests that NBP/TiO2 nanostructures function as a promising anticancer agent in combination with proteasome inhibitors.

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Combined autophagy and proteasome inhibition

Cited by 323 publications

References 42 publications

Targeting proteasome ubiquitin receptor Rpn13 in multiple myeloma

Targeting proteasome ubiquitin receptor Rpn13 in multiple myeloma

Development of fluorescent peptide substrates and assays for the key autophagy-initiating cysteine protease enzyme, ATG4B

Titania‐Coated Gold Nano‐Bipyramids for Blocking Autophagy Flux and Sensitizing Cancer Cells to Proteasome Inhibitor‐Induced Death

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