Oncotarget

Research Papers:

Hydroxychloroquine potentiates carfilzomib toxicity towards myeloma cells

Katarzyna Baranowska, Kristine Misund, Kristian K. Starheim, Toril Holien, Ida Johansson, Sagar Darvekar, Glenn Buene, Anders Waage, Geir Bjørkøy, _ Anders Sundan

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Abstract

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

Correspondence to:

Geir Bjørkøy, 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.

Author Information

Katarzyna Baranowska

Kristine Misund

Kristian K. Starheim

Toril Holien

Ida Johansson

Sagar Darvekar

Glenn Buene

Anders Waage

Geir Bjørkøy
Primary Contact  _

Anders Sundan


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