Calcium channel blocker verapamil enhances endoplasmic reticulum stress and cell death induced by proteasome inhibition in myeloma cells.
The proteasome inhibitor bortezomib is clinically approved for the treatment of multiple myeloma. However, long-term remissions are difficult to achieve, and myeloma cells often develop secondary resistance to proteasome inhibitors. We recently demonstrated that the extraordinary sensitivity of myeloma cells toward bortezomib is dependent on their extensive immunoglobulin synthesis, thereby triggering the terminal unfolded protein response (UPR). Here, we investigated whether verapamil, an inhibitor of the multidrug resistance (MDR) gene product, can enhance the cytotoxicity of bortezomib. The combination of bortezomib and verapamil synergistically decreased the viability of myeloma cells by inducing cell death. Importantly, bortezomib-mediated activation of major UPR components was enhanced by verapamil. The combination of bortezomib and verapamil resulted in caspase activation followed by poly(ADP-ribose) polymerase cleavage, whereas nuclear factor kappaB (NF-kappaB) activity declined in myeloma cells. Also, we found reduced immunoglobulin G secretion along with increased amounts of ubiquitinylated proteins within insoluble fractions of myeloma cells when using the combination treatment. Verapamil markedly induced reactive oxygen species production and autophagic-like processes. Furthermore, verapamil decreased MDR1 expression. We conclude that verapamil increased the antimyeloma effect of bortezomib by enhancing ER stress signals along with NF-kappaB inhibition, leading to cell death. Thus, the combination of bortezomib with verapamil may improve the efficacy of proteasome inhibitory therapy.
Meister
Silke
S
IZKF N2, Nikolaus-Fiebiger-Center of Molecular Medicine, University of Erlangen-Nuremberg, Erlangen, Germany.
Frey
Benjamin
B
Lang
Veronika R
VR
Gaipl
Udo S
US
Schett
Georg
G
Schlötzer-Schrehardt
Ursula
U
Voll
Reinhard E
RE
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000008:administration & dosage; D013312:Stress, Physiological / Q000187:drug effects; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D056811:Unfolded Protein Response / Q000187:drug effects* / Q000502:physiology; D014700:Verapamil / Q000008:administration & dosage / Q000494:pharmacology*
D001897:Boronic Acids; D002121:Calcium Channel Blockers; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D014700:Verapamil