Copolymères solubles inhibiteurs de l'angiogenèse in vitro

Abstract

Water-soluble statistic copolymers composed of sodium styrene sulfonate (NaSS) and methacrylic acid (MA) were synthesized. They inhibited adherence and proliferation of human breast cancer cells MCF7. One polymer, chemical composition 30%mol MA and 70%mol NaSS (MA–NaSS 30–70), shown a growth inhibition rate of 42% at day 6 at 100 μg/mL. Effects on human endothelial cells were then tested. The activity of four polymers MA–NaSS 30–70, 50–50, 60–40 and poly(NaSS), at various concentrations on human umbilical vein endothelial cells (HUVECs) was investigated. Results showed an inhibition of 80% on HUVECs growth. The effect of copolymers on cell morphology was investigated. When HUVECs were cultivated in the presence of MA–NaSS 30–70 and poly(NaSS) at 10 μg/mL, cells remained rounded-shaped and did not spread. Moreover, cell area was systematically smaller for cells cultivated in the presence of copolymers versus control. The cytoskeleton of HUVECs was sensitively affected. Actin stress fibers were neither elongated nor well differentiated and the number of focal contacts was dramatically decreased in comparison with control. The effect on angiogenesis was studied. After 24 hs of contact with MA–NaSS 30–70 at 10 μg/mL, HUVECs did not form tubules. In contrast, tubules were numerous and elongated on control samples. The expression of integrins mediating HUVECs adhesion or angiogenesis was studied. DNA electrophoresis of adherent and non-adherent cells were performed after 72 hours of incubation with MA–NaSS 30–70. For adherent cells β 1, β 3, and α V were less expressed α 5 was more expressed and α 2 expression was unchanged when compared to the controls. For non adherent cells β 1and α 5 were more expressed than in controls and α 2, α V and β 3 were almost the same as control. Our copolymers are able to in vitro inhibit cancer cells growth and angiogenesis. Their activity is based on the inhibition of integrins mediated cell adherence to the extracellular matrix.