Dipalmitoylation of radicicol results in improved efficacy against tumor growth and angiogenesis in vivo.
Tumor-related angiogenesis is likely to be a potential target for the treatment of cancer. One key to develop this angiostatic strategy would be to find useful angiogenesis inhibitors. Here we report the effects of radicicol, a microbial angiogenesis inhibitor that we previously identified using the chorioallantoic membrane assay, and its novel analog, 14,16-dipalmitoyl-radicicol, on tumor angiogenesis and growth. As expected for agents containing a penolic hydroxyl group, systemic administration of radicicol had little or no effect on neovascularization triggered by a M5076 mouse tumor cell line or a RMT-1 rat mammary carcinoma cell line established from autochthonous rat mammary tumors induced by 7,12-dimethylbenz[a]anthracene in a mouse dorsal air sac assay system. The agent did not show growth-inhibitory activity against either transplantable M5076 tumors or autochthonous 7,12-dimethylbenz[a]anthracene-induced rat mammary tumors. In contrast, 14,16-dipalmitoyl-radicicol potently suppressed tumor angiogenesis and growth in these experimental models. Furthermore, the analog significantly prolonged the survival rate of M5076-implanted mice. Although not stronger than radicicol, it dose-dependently inhibited embryonic angiogenesis in the chorioallantoic membrane assay, the dose required for half-maximal inhibition (ID(50)) value being 23 microg (27 nmol) per egg, and showed concentration-dependent antiproliferative activity against microvascular endothelial cells in vitro. These data suggest that 14,16-dipalmitoyl-radicicol is a promising antitumor agent with antiangiogenic activity.
Oikawa
Tsutomu
T
Medical Research and Development Center, The Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo 113-8613, Japan. oikawa-t@kuhs.ac.jp
Onozawa
Chizuko
C
Kuranuki
Sachi
S
Igarashi
Yasuhiro
Y
Sato
Mayumi
M
Ashino
Hiromi
H
Shimamura
Mariko
M
Toi
Masakazu
M
Kurakata
Shinichi
S
D000400:Air Sacs / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry*; D005260:Female; D018942:Macrolides / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D015996:Survival Rate
D000970:Antineoplastic Agents; D005229:Fatty Acids, Monounsaturated; D018942:Macrolides; C008757:palmitoleic acid; C035359:monorden