4-[3,5-Bis(trimethylsilyl)benzamido] benzoic acid (TAC-101) induces apoptosis in colon cancer partially through the induction of Fas expression.
BACKGROUND
4-[3,5-Bis (trimethylsilyl) benzamido] benzoic acid (TAC-101) is a novel retinobenzoic acid derivative, which has a specific binding affinity to the retinoic acid receptors (RAR)-alpha and -beta. Apoptotic induction by TAC-101 was investigated using a rat hepatic metastatic model of rat RCN-9 colon cancer cells in vivo and FACScan analysis with the DLD-1 human colon cancer cell line in vitro.


METHODS
Hepatic metastatic tumors were induced using intra-portal injection of RCN-9 cells into F344 rats in vivo. TAC-101 (8 mg/kg) was orally administered for 5 consecutive days a week for 4 weeks. Subsequently, hepatic tumors were counted after laparotomy. Apoptotic index (A.I.) in the hepatic tumors was evaluated using immunohistochemistry for single-stranded DNA. The proliferative index (P.I.), Fas and Fas ligand were also immunohistochemically evaluated. Moreover, evaluation of apoptosis by TAC-101 in vitro using FACScan analysis was performed in the DLD-1 human colon cancer cell line.


RESULTS
Oral administration of TAC-101 resulted in a significant inhibition of hepatic metastasis without weight loss of the rats. TAC-101 significantly decreased P. I. but increased A. I. in the hepatic metastatic tumors. TAC-101 did not affect the expression of Fas ligand, but obviously increased the expression of Fas in the metastatic tumors. Moreover, TAC-101 induced early apoptosis in DLD-1 cells in a time-dependent manner in vitro.


CONCLUSIONS
These findings suggest that TAC-101 inhibits hepatic metastasis of colon cancer and induces apoptosis partially through enhanced Fas expression.
Sako
Tatsuhiko
T
Department of Surgery 1, University of Occupational and Environmental Health, School of Medicine, Yahatanisi-ku, Kitakyushu 807-8555, Japan.
Nakayama
Yoshifumi
Y
Minagawa
Noritaka
N
Inoue
Yuzuru
Y
Onitsuka
Koji
K
Katsuki
Takefumi
T
Tsurudome
Yosuke
Y
Shibao
Kazunori
K
Hirata
Keiji
K
Nagata
Naoki
N
Ohie
Shinji
S
Kohno
Kimitoshi
K
Itoh
Hideaki
H
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001565:Benzoates / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000139:chemically induced / Q000556:secondary; D008297:Male; D009362:Neoplasm Metastasis / Q000517:prevention & control; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors; D014297:Trimethylsilyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D019014:fas Receptor / Q000187:drug effects / Q000378:metabolism*
D001565:Benzoates; C112689:TAC 101; D014297:Trimethylsilyl Compounds; D019014:fas Receptor