Hydroxychloroquine potentiates carfilzomib toxicity towards myeloma cells
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Katarzyna Baranowska1,*, Kristine Misund1,*, Kristian K. Starheim1,2, Toril Holien1, Ida Johansson2,3, Sagar Darvekar1, Glenn Buene1, Anders Waage1,4, Geir Bjørkøy2,5, Anders Sundan1,2
1Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway
2CEMIR–Center of Molecular Inflammation Research, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway
3Department of Laboratory Medicine, Children’s and Women’s Health, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway
4Department of Hematology, St. Olav’s University Hospital, Trondheim, Norway
5Department of Medical Laboratory Technology, Faculty of Technology, Norwegian University of Science and Technology, Trondheim, Norway
*These authors have contributed equally to this study
Geir Bjørkøy, email: email@example.com
Anders Sundan, email: firstname.lastname@example.org
Keywords: myeloma, proteasome, carfilzomib, bortezomib, resistance
Received: June 03, 2016 Accepted: September 02, 2016 Published: September 23, 2016
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.
Kristian K. Starheim
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