Suppression of cancer cachexia by 20S,21-epoxy-resibufogenin-3-acetate-a novel nonpeptide IL-6 receptor antagonist.
While screening for novel IL-6 inhibitors, we synthesized 20S,21-epoxy-resibufogenin-3-acetate (ERBA). ERBA dose-dependently suppressed IL-6-induced cell growth with an IC(50) value of 5.3 microM and caused a parallel rightward shift of dose-response curves to IL-6. Analysis of data yields a pA2 of 5.83 and a slope of 0.99. ERBA did not affect IL-2-, IL-3-, and GCSF-dependent cell growth, or tumor necrosis factor alpha-induced growth suppression, nor did ERBA affect osteoclast formation induced by IL-11, leukemia inhibitory factor, and 1alpha,25-dihydroxyvitamin D(3). Receptor assay showed that ERBA dose-dependently suppressed IL-6 binding to IL-6 receptor (IL-6R). Furthermore, no band existing at the position of IL-6R in Western blots of ERBA-treated cells when stimulated with IL-6:ERBA suppresses IL-6 activity by blocking the binding of IL-6 to IL-6R. In an experimental model of colon 26-induced cancer cachexia, ERBA markedly inhibited body weight loss. ERBA is a specific small molecule with IL-6R-antagonist activity.
Enomoto
Akiko
A
Fancl Co. Ltd. Central Research Laboratory, 12-13 Kamishinano, Totsuka-ku, Yokohama 244-0806, Japan.
Rho
Mun-Chual
MC
Fukami
Akiko
A
Hiraku
Osamu
O
Komiyama
Kanki
K
Hayashi
Masahiko
M
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001835:Body Weight / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002018:Bufanolides / Q000008:administration & dosage*; D002100:Cachexia / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003110:Colonic Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D015850:Interleukin-6 / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012886:Skull / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016896:Treatment Outcome
C493789:20,21-epoxyresibufogenin-3-acetate; D000970:Antineoplastic Agents; D002018:Bufanolides; D015850:Interleukin-6; D019947:Receptors, Interleukin-6