Blockage of interleukin-6 signaling with 6-amino-4-quinazoline synergistically induces the inhibitory effect of bortezomib in human U266 cells.
The transcription factor nuclear factor-kappa B (NF-kappaB) regulates the transcription of a number of genes involved in a variety of cellular responses, including cell survival, inflammation, and differentiation. NF-kappaB is activated by a variety of stimuli, proinflammatory cytokines, mitogens, growth factors, and stress-inducing agents. Aberrant NF-kappaB expression is considered to be one of the oncogenic factors of cancer and the constitutive activation of NF-kappaB is observed in several hematologic disorders [classic Hodgkin's lymphoma, diffuse large B cell lymphoma, and multiple myeloma (MM)], and the modulation of NF-kappaB activation is emerging as a promising novel anticancer therapeutic strategy.Therefore, we focused on the regulation of NF-kappaB activation in MM. When U266 cells were treated with 6-amino-4-quinazoline, an NF-kappaB activation inhibitor, we determined that it most effectively blocked the interleukin (IL)-6-induced activation of MAPK and JAK/STAT pathways among different signaling inhibitors. The results of the luciferase assay indicated that 6-amino-4-quinazoline inhibited NF-kappaB activation with diminished NF-kappaB protein bound to NF-kappaB DNA binding sites. In addition, 6-amino-4-quinazoline suppressed the production of IL-6, which affected MM cell proliferation. Furthermore, combined treatment with bortezomib and 6-amino-4-quinazoline effectively inhibited the IL-6 and soluble IL-6R-induced activation of STAT3 and extracellular signal-regulated kinase phosphorylation. Our data showed that the inhibition of NF-kappaB activation abrogated MM cell proliferation induced by the IL-6 pathway, and might represent a promising therapeutic strategy for the treatment of MM.
Park
Juwon
J
Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
Ahn
Kwang-Sung
KS
Bae
Eun-Kyung
EK
Kim
Byung-Su
BS
Kim
Byoung Kook
BK
Lee
Young-Yiul
YY
Yoon
Sung-Soo
SS
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D017930:Genes, Reporter / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D015851:Interleukin-7 / Q000037:antagonists & inhibitors; D008156:Luciferases / Q000378:metabolism; D009101:Multiple Myeloma / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D011719:Pyrazines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D000093242:Interleukin-6 Inhibitors
D000970:Antineoplastic Agents; D001897:Boronic Acids; D000069286:Bortezomib; D048049:Extracellular Signal-Regulated MAP Kinases; D015850:Interleukin-6; D015851:Interleukin-7; D008156:Luciferases; D016328:NF-kappa B; D011719:Pyrazines; D011799:Quinazolines; D050796:STAT3 Transcription Factor; D000093242:Interleukin-6 Inhibitors; C532264:6-amino-4-quinazoline; C494086:STAT3 protein, human