Combination chemotherapy increases cytotoxicity of multiple myeloma cells by modification of nuclear factor (NF)-κB activity.
The nuclear factor (NF)-κB signaling pathway is critical in myeloma cell proliferation, inhibition of apoptosis, and emergence of therapy resistance. The chemotherapeutic drugs, dexamethasone (Dex) and bortezomib (BTZ), are widely used in clinical protocols for multiple myeloma (MM) and inhibit the NF-κB signaling pathway by distinct mechanisms. This study evaluates the efficacy of combination therapy with Dex and BTZ and investigates the mechanistic underpinning of endogenous and therapy-induced NF-κB activation in MM. Human myeloma cells and bone marrow stromal cells (BMSCs) were used in monocultures and cocultures to determine the cytotoxic effects of Dex and/or BTZ. Our results show that combined treatment of Dex with BTZ enhanced direct apoptosis of drug-sensitive and drug-resistant myeloma cells. In the presence of BMSCs, Dex plus BTZ combination inhibited ionizing radiation-induced interleukin 6 secretion from BMSCs and induced myeloma cytotoxicity. Mechanistically, Dex treatment increased IκBα protein and mRNA expression and compensated for BTZ-induced IκBα degradation. Dex plus BTZ combination inhibited basal and therapy-induced NF-κB activity with cytotoxicity in myeloma cells resistant to BTZ. Furthermore, combination therapy downregulated the NF-κB-targeted gene expression of interleukin 6 and manganese superoxide dismutase, which can induce chemo- and radio-resistance in MM. This study provides a mechanistic rationale for combining the NF-κB-targeting drugs Dex and BTZ in myeloma therapy and supports potential combinations of these drugs with radiotherapy and additional chemotherapeutic drugs for clinical benefit in MM.
Free Radical and Radiation Biology Program, Department of Radiation Oncology, The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA.
Kelley
K
Salem
Charles O
CO
Brown
Jeanine
J
Schibler
Apollina
A
Goel
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D000069286:Bortezomib; D018920:Coculture Techniques; D003907:Dexamethasone / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000187:drug effects; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects
D001897:Boronic Acids; C508600:IL6 protein, human; D015850:Interleukin-6; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D003907:Dexamethasone; D013482:Superoxide Dismutase