INHIBITION OF RAT SMOOTH MUSCLE CELL PROLIFERATION BY NEW POTENTIAL TOPOISOMERASEs INHIBITORS

Accumulation of smooth muscle cells (SMC) of the arterial wall in response to local injury is an important aetiologic factor of vascular proliferative disorders such as atherosclerosis and restenosis after angioplasty. Thus a rational approach to reduce the smooth muscle in the vessel wall is to target intracellular mechanisms regulating cell proliferation active during the progression stage of lesion development. DNA topoisomerase I and II constitute a class of nuclear proteins involved in DNA replication that catalyze the passage of individual DNA strands or double helices through one another. This reaction is known to be required for S phase transition of the cell cycle during cellular duplication, and the topoisomerase I inhibitor topotecan has been previously shown to effectively inhibits SMC proliferation and migration. On the basis of this premises the aim of this study was to develop new pharmacological inhibitors of topoisomerase II and study their antiproliferative effect on rat SMC. 18 different compounds, either chemically synthesized or extracted, were tested. 8 compounds show a significant antiproliferative activity. In particular 3 of them (UR1-12, UR5-03 and UR5-08) were able to interfere with SMC proliferation with IC50-values of 5.98, 4.41, and 1.61 M, respectively. Cell cycle analysis show that incubation with UR1-12, UR5-03 and UR5-08 leads to the accumulation of cells at G2/M phase of the cell cycle in a concentration-dependent manner. Future studies will be performed to directly investigate the inhibitory activity of the tested compounds on topoisomerase II activity in vitro, and their action on SMC proliferation after perivascular manipulation of rabbit carotid artery.