Hydroxychloroquine potentiates carfilzomib toxicity towards myeloma cells.
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.
Department of Cancer Research and Molecular Medicine, Faculty of Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
Katarzyna
K
Baranowska
Department of Cancer Research and Molecular Medicine, Faculty of Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
Kristine
K
Misund
Department of Cancer Research and Molecular Medicine, Faculty of Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.|CEMIR-Center of Molecular Inflammation Research, Faculty of Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
Kristian K
KK
Starheim
Department of Cancer Research and Molecular Medicine, Faculty of Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
Toril
T
Holien
CEMIR-Center of Molecular Inflammation Research, Faculty of Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.|Department of Laboratory Medicine, Children's and Women's Health, Faculty of Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
Ida
I
Johansson
Department of Cancer Research and Molecular Medicine, Faculty of Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
Sagar
S
Darvekar
Department of Cancer Research and Molecular Medicine, Faculty of Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
Glenn
G
Buene
Department of Cancer Research and Molecular Medicine, Faculty of Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.|Department of Hematology, St. Olav's University Hospital, Trondheim, Norway.
Anders
A
Waage
CEMIR-Center of Molecular Inflammation Research, Faculty of Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.|Department of Medical Laboratory Technology, Faculty of Technology, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
Geir
G
Bjørkøy
Department of Cancer Research and Molecular Medicine, Faculty of Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.|CEMIR-Center of Molecular Inflammation Research, Faculty of Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
Anders
A
Sundan
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects; D000069286:Bortezomib / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D006886:Hydroxychloroquine / Q000494:pharmacology* / Q000627:therapeutic use; D008247:Lysosomes / Q000187:drug effects; D018942:Macrolides / Q000494:pharmacology; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D061251:Primary Cell Culture; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D000071456:Sequestosome-1 Protein / Q000378:metabolism
D004791:Enzyme Inhibitors; D018942:Macrolides; D009842:Oligopeptides; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D006886:Hydroxychloroquine; D000069286:Bortezomib; C524865:carfilzomib; C040929:bafilomycin A1; D046988:Proteasome Endopeptidase Complex
bortezomib; carfilzomib; myeloma; proteasome; resistance
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