4-[3,5-Bis(trimethylsilyl)benzamido] benzoic acid inhibits angiogenesis in colon cancer through reduced expression of vascular endothelial growth factor.
4-[3,5-bis(trimethylsilyl)benzamido] Benzoic acid (TAC-101) has potent antiproliferative, antiangiogenic, and antitumor effects in vitro and in vivo. These effects might be due to TAC-101 binding to retinoic acid receptor alpha (RAR-alpha) and interfering with the binding of activator protein-1 (AP-1) to DNA. However, little is known about the detailed mechanism of TAC-101 function. We investigated the mechanism of the antiangiogenic effect of TAC-101 using a rat hepatic metastatic model in vivo and DLD-1 human colon cancer cells in vitro. Liver metastases were induced by portal injection of RCN-9 rat colonic cancer cells into F344 rats. TAC-101 (8 mg/kg) was orally administered 5 days per week for 4 weeks and then hepatic tumors were immunohistochemically evaluated for microvessel density (MVD) and vascular endothelial growth factor (VEGF). TAC-101 significantly reduced both MVD and VEGF expression. Northern blot analysis and ELISA indicated that TAC-101 efficiently inhibited production of VEGF mRNA and protein in DLD-1 cells in a time- and dose-dependent manner. These findings suggest that TAC-101 may inhibit progression and metastasis in colon cancer by interfering with tumor production of VEGF.
Minagawa
Noritaka
N
Department of Surgery 1, University of Occupational and Environmental Health, School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku, Kita-kyushu 807-8555, Japan. minagawa@med.uoeh-u.ac.jp
Nakayama
Yoshifumi
Y
Inoue
Yuzuru
Y
Onitsuka
Koji
K
Katsuki
Takefumi
T
Tsurudome
Yosuke
Y
Shibao
Kazunori
K
Hirata
Keiji
K
Sako
Tatsuhiko
T
Nagata
Naoki
N
Ohie
Shinji
S
Kohno
Kimitoshi
K
Itoh
Hideaki
H
D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D014297:Trimethylsilyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
D020533:Angiogenesis Inhibitors; D001565:Benzoates; C112689:TAC 101; D014297:Trimethylsilyl Compounds; D042461:Vascular Endothelial Growth Factor A