Search for the molecular mechanism of action of a novel synthetic retinoid, acyclic retinoid

无环类维生素A（Acyclic retinoid，ACR）是一种新型的人工合成类维生素A，可预防原发性肝癌切除术后的复发，但ACR发挥抗肿瘤作用的分子机制尚不清楚。在本研究中，我们发现ACR对人肝癌细胞的生长抑制与诱导p21 β<CIP1>和抑制cyclin D1的表达有关。我们还发现ACR激活维甲酸受体β，并诱导<CIP1>人肝癌、头颈部和食管鳞状细胞癌细胞中p21 α的转录激活。ACR的这些新的作用表明，这种药物可能是有用的化学预防和治疗各种恶性肿瘤。此外，ACR和OSI461（一种有效的依昔舒林衍生物）的组合对HepG2细胞的生长具有协同抑制作用。这一结果表明，ACR和OSI 461的组合可能是一个有效的方案，用于人类肝癌和可能的其他恶性肿瘤的化学预防和化学治疗。

Acyclic retinoid(ACR), a novel synthetic retinoid, can prevent the recurrence of hepatomas after surgical resection of primary tumors, but the molecular mechanisms by which ACR exerts anti-tumor effects are not known. In the present studies we found that growth inhibition of human hepatoma cells by ACR is associated with induction of p21^<CIP1> and inhibition of expression of cyclin D1. We also found that ACR activates retinoic acid receptor β and induces transcriptional activation of p21^<CIP1> in human hepatoma, and head and neck and esophageal squamous cell carcinoma cells. These novel effects of ACR suggest that this agent might be useful in the chemoprevention and therapy of various malignancies. Furthermore, the combination of ACR and OSI461, a potent derivative of exisulind, exerted synergistic inhibition of the growth of HepG2 cells. This result suggests that the combination of ACR and OSI461 might be an effective regimen for the chemoprevention and chemotherapy of human hepatoma and possibly other malignancies.