Combined autophagy and proteasome inhibition
| العنوان: | Combined autophagy and proteasome inhibition |
|---|---|
| المؤلفون: | Daniel F. Heitjan, Thomas M. Paul, Janeen Kaplan, Laura Pontiggia, James E. Bradner, Lisa E. Davis, Emma C. Scott, Yunyoung C. Chang, Kay See Tan, Charles W. Nichols, Dan T. Vogl, David L. Porter, Gayle Mallon, Ravi K. Amaravadi, Shengfu Piao, Edward A. Stadtmauer, Reshma Rangwala |
| المصدر: | Autophagy. 10:1380-1390 |
| بيانات النشر: | Informa UK Limited, 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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. |
| تدمد: | 1554-8635 1554-8627 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::11572d3867c26d032b58bfcf22e754a0Test https://doi.org/10.4161/auto.29264Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....11572d3867c26d032b58bfcf22e754a0 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15548635 15548627 |
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