4-[3,5-Bis(trimethylsilyl)benzamido] benzoic acid (TAC-101) induces apoptosis in colon cancer partially through the induction of Fas expression.

Abstract

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.

MATERIALS AND 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.

CONCLUSION:

These findings suggest that TAC-101 inhibits hepatic metastasis of colon cancer and induces apoptosis partially through enhanced Fas expression.

• Authors: Tatsuhiko Sako, Yoshifumi Nakayama, Noritaka Minagawa, Yuzuru Inoue, Koji Onitsuka, Takefumi Katsuki, Yosuke Tsurudome, Kazunori Shibao, Keiji Hirata, Naoki Nagata, Shinji Ohie, Kimitoshi Kohno, Hideaki Itoh
• Journal: In vivo (Athens, Greece) (In Vivo) 2005 Jan-Feb Vol. 19 Issue 1 Pg. 125-32 ISSN: 0258-851X [Print] Greece
• PMID: 15796164 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzoates
• TAC 101
• Trimethylsilyl Compounds
• fas Receptor

Topics

• Adenocarcinoma (metabolism, pathology)
• Administration, Oral
• Animals
• Apoptosis (drug effects)
• Benzoates (administration & dosage, pharmacology)
• Cell Line, Tumor
• Colonic Neoplasms (metabolism, pathology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Humans
• Immunohistochemistry
• Liver Neoplasms (chemically induced, secondary)
• Male
• Neoplasm Metastasis (prevention & control)
• Rats
• Rats, Inbred F344
• Time Factors
• Trimethylsilyl Compounds (administration & dosage, pharmacology)
• fas Receptor (drug effects, metabolism)