INHIBITION OF CELL-PROLIFERATION AND INDUCTION OF APOPTOSIS BY THE RETINOID AHPN IN HUMAN LUNG-CARCINOMA CELLS

In this study, we investigated the effect of the novel retinoid 6-[3-( 1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN/CD43 7) on the growth of human lung carcinoma cell lines. AHPN inhibits the proliferation of all cell lines tested, irrespective of the lung tumo r type, in a concentration-and time-dependent manner. A dramatic reduc tion in cell number was observed in adenocarcinoma H460 cells, and was shown to be related to an induction of apoptosis. Bromodeoxyuridine ( BrdU) incorporation and flow-cytometric analyses indicated that treatm ent of H460 cells with AHPN induces cell-cycle arrest at the G(1) phas e. We therefore investigated the effect of AHPN on several regulatory proteins of the CI phase of the cell-cycle. The cell-cycle arrest indu ced by AHPN was accompanied by an inhibition of the hyperphosphorylati on of the retinoblastoma (Rb) protein, an indication of G, arrest. Fur thermore, two cyclin-dependent kinases, cdk2 and cdk4, which are norma lly involved in the phosphorylation of Rb, were shown to have decrease d activity. In some cell lines, the decrease in cdk activity may be pa rtly related to an increase in p21(WAF1/Cip1) (p21), an inhibitor of c yclin-dependent kinases. No changes were observed in the cyclin-depend ent kinase inhibitor p27(Kip1). Th, observed increase in p53 in respon se to AHPN could at least to some extent be responsible for the increa sed levels of p21. The increase in p53 expression was found to be regu lated at a post-transcriptional level. Our results suggest that the gr owth inhibition of certain lung carcinoma noma cell lines by AHPN is a t least partly related to an increase in p21. However, in other cell l ines, different mechanisms appear to be involved. The specificity with which AKPN and other retinoids induce growth arrest and p21 expressio n indicates that the action of AHPN is not mediated by RAR or RXR rece ptors, but involves a novel signaling pathway.