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)-· and -‚. 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 immuno- histochemistry 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. In colon cancer, hepatic metastasis is a critical problem, which affects mortality rate. A reduction in hepatic metastasis would lead to an improved prognosis for patients with advanced colon cancer. Recently, retinoic acid (RA) has shown to be a