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Combined autophagy and proteasome inhibition
- Source :
- Autophagy. 10:1380-1390
- Publication Year :
- 2014
- Publisher :
- Informa UK Limited, 2014.
-
Abstract
- The efficacy of proteasome inhibition for myeloma is limited by therapeutic resistance, which may be mediated by activation of the autophagy pathway as an alternative mechanism of protein degradation. Preclinical studies demonstrate that autophagy inhibition with hydroxychloroquine augments the antimyeloma efficacy of the proteasome inhibitor bortezomib. We conducted a phase I trial combining bortezomib and hydroxychloroquine for relapsed or refractory myeloma. We enrolled 25 patients, including 11 (44%) refractory to prior bortezomib. No protocol-defined dose-limiting toxicities occurred, and we identified a recommended phase 2 dose of hydroxychloroquine 600 mg twice daily with standard doses of bortezomib, at which we observed dose-related gastrointestinal toxicity and cytopenias. Of 22 patients evaluable for response, 3 (14%) had very good partial responses, 3 (14%) had minor responses, and 10 (45%) had a period of stable disease. Electron micrographs of bone marrow plasma cells collected at baseline, after a hydroxychloroquine run-in, and after combined therapy showed therapy-associated increases in autophagic vacuoles, consistent with the combined effects of increased trafficking of misfolded proteins to autophagic vacuoles and inhibition of their degradative capacity. Combined targeting of proteasomal and autophagic protein degradation using bortezomib and hydroxychloroquine is therefore feasible and a potentially useful strategy for improving outcomes in myeloma therapy.
- Subjects :
- Adult
Male
Protein degradation
Pharmacology
Biology
Bortezomib
Refractory
Recurrence
hemic and lymphatic diseases
Antineoplastic Combined Chemotherapy Protocols
Autophagy
medicine
Humans
Molecular Biology
Multiple myeloma
Aged
Dose-Response Relationship, Drug
Hydroxychloroquine
Cell Biology
Middle Aged
medicine.disease
Boronic Acids
medicine.anatomical_structure
Proteasome
Pyrazines
Proteasome inhibitor
Female
Bone marrow
Clinical Research Paper
Multiple Myeloma
Proteasome Inhibitors
medicine.drug
Subjects
Details
- ISSN :
- 15548635 and 15548627
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- Autophagy
- Accession number :
- edsair.doi.dedup.....11572d3867c26d032b58bfcf22e754a0
- Full Text :
- https://doi.org/10.4161/auto.29264