Abstract #5310: Contribution of AP-1 interference induced by TAC-101 to tumor growth suppression in a hepatocellular carcinoma model

Abstract

TAC-101 (4-[3,5-bis(trimethylsilyl)benzamido] benzoic acid) is a synthetic ligand for retinoic acid receptor-alpha (RAR \#945; ). TAC-101 induced transcriptional activation of RAR, resulting in marked elevation of a retinoic acid response gene RAR \#946; in human hepatocellular carcinoma cell line JHH-7. TAC-101 also significantly repressed the transcriptional activity of AP-1 in JHH-7 cells. On the other hand, RAR transcriptional activation, RAR \#946; induction, and AP-1 inhibition were not seen in JHH-6 cells, another RAR \#945; expressing human HCC cell line with constitutive activation of AP-1. Interleukin-8 (IL-8), one of the AP-1-regulated factors which correlate with poor prognosis of HCC patients was found to be highly expressed in JHH-7 cells. TAC-101 reduced IL-8 production and it inhibited the progression of HCC in the orthotropic mice xenograft model with decrease of the tumor IL-8 level. These results suggest that down-regulation of the extra-cellular AP-1-related factor via the induction of retinoid signal enhance the pharmacological effect of TAC-101 against HCC and it can be a useful surrogate biomarker of therapeutic efficacy.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5310.