AROTINOID MOFAROTENE (RO40-8757) UP-REGULATES P21 AND P27 DURING GROWTH-INHIBITION OF PANCREATIC-CANCER CELL-LINES

Effective chemotherapy for pancreatic cancer is urgently needed. The a nti-proliferative activity of a new retinoid, mofarotene (RO40-8757), was compared with that of other retinoids, such as all trans-retinoic acid, 13-cis retinoic acid and 9-cis retinoic acid, on 9 pancreatic ca ncer cell lines in relation to the effects on various cell cycle-regul ating factors. After treatment with each retinoid, anti-proliferative effect was determined by the MTT method and expression of cell cycle-r egulating factors, such as cyclins (D-1, E and A), cyclin-dependent ki nases (2 and 4), cyclin-dependent kinase inhibitors (p21 and p27) and retinoblastoma protein, was analyzed by Western blotting. Mofarotene s howed half-maximal inhibition of cell proliferation at concentrations between 0.14 x 10(-6) and 3.8 x 10(-6) mol/l with little cytotoxicity. In contrast, the other retinoids did not inhibit the growth of all ce ll lines by over 50% compared to controls. A marked increase in the fr action of cells in G(1) phase of the cell cycle was observed after mof arotene treatment; this was associated with marked up-regulation of p2 1/p27 and a shift of retinoblastoma protein into the hypophosphorylate d form. In conclusion, mofarotene inhibits the growth of pancreatic ca ncer cells by inducing G(1)-phase cell cycle-inhibitory factors (p21, p27 and hypophosphorylated form of Rb protein) and is considered to be a useful agent for pancreatic cancer treatment. (C) 1997 Wiley-Liss, Inc.