ANTIPROLIFERATIVE AND DIFFERENTIATING EFFECTS OF BENZODIAZEPINE RECEPTOR LIGANDS ON B16 MELANOMA-CELLS

In this study, we evaluated the effect of several ligands active at th e central-type and peripheral-type benzodiazepine receptor (BzR) (clon azepam, diazepam, PK11195 and Ro5-4864) on the growth and differentiat ion of B16 melanoma cells. All tested BzR ligands were able to suppres s proliferation of the cells at the micromolar range and in a concentr ation-dependent manner. However, agents selectively active at the peri pheral-type BzR (PK11195 and Ro5-4864) exhibited more potent antiproli ferative activity. In addition, the BzR ligands were demonstrated to a ffect the cell cycle by reducing the percent of cells in the S phase a nd increasing the percent in the G2/M phase. BzR ligands induced cellu lar phenotypic alterations, which have been previously shown to be ass ociated with melanoma cell differentiation. These alterations included : marked morphological changes, enhancement of melanogenesis, lipid ac cumulation and increase in the activity of gamma glutamyl transpeptida se. All BzR ligands induced a marked reduction in the concentration of UTP and most of them did the same in GTP and CTP, while ATP levels we re not significantly altered. In summary, BzR ligands (clonazepam, dia zepam, PK11195 and Ro5-4864) were found to exert antitumor effects in B16 melanoma cells. These findings encourage further studies of a poss ible therapeutic potential of BzR ligands in treatment of melanoma. (C ) 1998 Elsevier Science Inc.