Investigation of the inhibitory mechanism of the hepatic metastasis in the colorectal carcinoma by synthesic retinoid, TAC-101

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The presence of hepatic metastasis is one of the most important prognostic factors in colorectal cancer. This suggests that more effective suppressor of the progression and metastasis of colon cancer would significantly improve prognosis. Recently, RA (retinoic acid) has shown to be a potentially powerful anti-cancer agent, and acts in several types of cancer therapy. The mechanism of RA's affect on tumors appears to be related to its effects on proliferation and differentiation of tumor cells. 4-[3,5-bis (trimethylsilyl) benzamido] benzoic acid (TAC-101) is a novel retinobenzoic acid derivative and has a specific binding affinity to the retinoic acid receptors (RAR)-α and -β. TAC-101 has potent anti-proliferative, anti-angiogenic, and anti-tumor effects in vitro and in vivo. However, little is known about the detailed mechanism of TAC-101 function.Here, we investigate the mechanism of the anti-angiogenic effect and apoptosis induction of TAC-101. Hepatic metastases were induced by por … More tal injection of RCN-9 rat colonic cancer cells into F344 rats. TAC-101 was orally administered 5 days per week for four weeks, then liver tumors were immunohistochemically evaluated for microvascular density (MVD) and vascular endothelial growth factor (VEGF). 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.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. 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.These findings suggest that TAC-101 may inhibit progression and metastasis in colon cancer by interfering with tumor production of VEGF. Moreover, TAC-101 may induced apoptosis partially through enhanced Fas expression. Less