Acyclic retinoid, a novel synthetic retinoid, induces growth inhibition, apoptosis, and changes in mRNA expression of cell cycle- and differentiation-related molecules in human colon carcinoma cells

摘要

Acyclic retinoid (ACR), a novel synthetic retinoid, has been demonstrated by us to inhibit the in vitro growth of human hepatoma cells, and this effect was associated with modification of cell cycle control molecules, suggesting that this agent may be useful in the chemoprevention and therapy of various types of malignancies. However, whether or not ACR exerts anticancer activities on human colon carcinoma cells has not yet been elucidated. The purpose of this study was to examine the inhibitory effects of ACR in human colon carcinoma cells and to characterize the molecular mechanism of action of this agent. ACR inhibited the growth of the HCT116 and SW480 human colon carcinoma cell lines with IC50 values of about 30 and 60 μM, respectively. ACR also induced G1-phase cell cycle arrest and apoptosis in these cell lines. When the HCT116 cells were treated with 5-25 μM ACR, there was a marked decrease in the cellular levels of cyclin D1 mRNA and an approximate 2.5- to 3-fold increase in those of p21CIP1 mRNA, and this induction occurred via a p53-independent mechanism. Furthermore, ACR induced a dose-dependent mRNA elevation of differentiation markers at concentrations of ACR that affect the levels of expression of p21CIP1. These novel results suggest that ACR inhibits cell proliferation by inducing G1 arrest and apoptosis and that cyclin D1 and p21CIP1 play critical roles in the molecular mechanisms of growth inhibition and differentiation induced by ACR. Collectively, these findings provide further evidence that ACR may be a potential agent for the chemoprevention and therapy of human colon cancer.