Hydroxychloroquine potentiates carfilzomib toxicity towards myeloma cells
| Autor: | Kristine Misund, Katarzyna Anna Baranowska, Geir Bjørkøy, Anders Sundan, Sagar Ramesh Darvekar, Toril Holien, Glenn Buene, Anders Waage, Kristian K. Starheim, Ida Johansson |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Oncology Pharmacology chemistry.chemical_compound 0302 clinical medicine immune system diseases hemic and lymphatic diseases Antineoplastic Combined Chemotherapy Protocols Sequestosome-1 Protein Enzyme Inhibitors Multiple myeloma Hematology carfilzomib Microscopy Confocal Bortezomib bortezomib Drug Synergism myeloma 030220 oncology & carcinogenesis Macrolides Multiple Myeloma Oligopeptides medicine.drug Research Paper Hydroxychloroquine medicine.medical_specialty Proteasome Endopeptidase Complex Primary Cell Culture Protein degradation resistance 03 medical and health sciences Internal medicine Cell Line Tumor medicine Autophagy Humans business.industry medicine.disease Molecular medicine Carfilzomib 030104 developmental biology proteasome chemistry Microscopy Fluorescence Drug Resistance Neoplasm Proteolysis Proteasome inhibitor business Lysosomes |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Katarzyna Baranowska 1, * , Kristine Misund 1, * , Kristian K. Starheim 1, 2 , Toril Holien 1 , Ida Johansson 2, 3 , Sagar Darvekar 1 , Glenn Buene 1 , Anders Waage 1, 4 , Geir Bjorkoy 2, 5 , Anders Sundan 1, 2 1 Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway 2 CEMIR–Center of Molecular Inflammation Research, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway 3 Department of Laboratory Medicine, Children’s and Women’s Health, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway 4 Department of Hematology, St. Olav’s University Hospital, Trondheim, Norway 5 Department of Medical Laboratory Technology, Faculty of Technology, Norwegian University of Science and Technology, Trondheim, Norway * These authors have contributed equally to this study Correspondence to: Geir Bjorkoy, email: geir.bjorkoy@ntnu.no Anders Sundan, email: anders.sundan@ntnu.no Keywords: myeloma, proteasome, carfilzomib, bortezomib, resistance Received: June 03, 2016 Accepted: September 02, 2016 Published: September 23, 2016 ABSTRACT Cells degrade proteins either by proteasomes that clinically are targeted by for example bortezomib or carfilzomib, or by formation of autophagosomes and lysosomal degradation that can be inhibited by hydroxychloroquine (HCQ). Multiple myeloma is unique among cancers because proteasomal inhibition has good clinical effects. However, some multiple myeloma patients display intrinsic resistance to the treatment and most patients acquire resistance over time. We hypothesized that simultaneous targeting both arms of protein degradation could be a way to improve treatment of multiple myeloma. Here we tested the combined effects of the lysosomal inhibitor HCQ and clinically relevant proteasome inhibitors on myeloma cell lines and primary cells. Carfilzomib and bortezomib both induced immunoglobulin-containing aggregates in myeloma cells. HCQ significantly potentiated the effect of carfilzomib in both cell lines and in primary myeloma cells. In contrast, HCQ had little or no effects on the toxicity of bortezomib. Furthermore, cells adapted to tolerate high levels of carfilzomib could be re-sensitized to the drug by co-treatment with HCQ. Thus, we show that inhibition of lysosomal degradation can overcome carfilzomib resistance, suggesting that the role of autophagy in myeloma cells is dependent on type of proteasome inhibitor. In conclusion, attempts should be made to combine HCQ with carfilzomib in the treatment of multiple myeloma. |
| Databáze: | OpenAIRE |
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