A novel NF-κB inhibitor improves glucocorticoid sensitivity of canine neoplastic lymphoid cells by up-regulating expression of glucocorticoid receptors.
Lymphoid neoplasms including lymphoma and leukemia are one of the most life-threatening disorders in dogs. Many lymphoid malignancies are well-treated with glucocorticoid (GC); however, GC resistance sometimes develops and its mechanism remains uncertain. Since constitutive activation of nuclear factor-κB (NF-κB) has been reported to play roles in lymphoid malignancies, we examined whether inhibition of NF-κB activity with a synthetic inhibitor IMD-0354 affected GC sensitivity of canine neoplastic lymphoid cells, CL-1 and GL-1. Dexamethasone failed to inhibit proliferation of these cells, in which low expression of glucocorticoid receptors (GR) was identified. In the presence of IMD-0354, GR expressions in CL-1 and GL-1 were increased, consequently dexamethasone inhibited their proliferation. These results indicated that GR expression might be down-regulated by spontaneous activation of NF-κB, resulting in GC resistance. Taken together, interference of NF-κB activity may have the synergistic effect in combination chemotherapy with GC for treatment against lymphoid malignancies.
Matsuda
A
A
Laboratory of Veterinary Molecular Pathology and Therapeutics, Division of Animal Life Science, Graduate School, Institute of Symbiotic Science and Technology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan.
Tanaka
A
A
Muto
S
S
Ohmori
K
K
Furusaka
T
T
Jung
K
K
Karasawa
K
K
Okamoto
N
N
Oida
K
K
Itai
A
A
Matsuda
H
H
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D015153:Blotting, Western / Q000662:veterinary; D003907:Dexamethasone / Q000494:pharmacology; D004283:Dog Diseases / Q000188:drug therapy* / Q000276:immunology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000378:metabolism / Q000662:veterinary*; D016399:Lymphoma, T-Cell / Q000188:drug therapy / Q000378:metabolism / Q000662:veterinary*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000662:veterinary; D015854:Up-Regulation / Q000187:drug effects
D001549:Benzamides; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; C492919:N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide; D003907:Dexamethasone