Parthenolide inhibits proliferation of vascular smooth muscle cells through induction of G0/G1 phase cell cycle arrest

Abstract

This study is to determine the effect of the natural product parthenolide, a sesquiterpene lactone isolated from extracts of the herb Tanacetum parthenium, on the proliferation of vascular smooth muscle cells (VSMCs). Rat aortic VSMCs were isolated and cultured in vitro, and treated with different concentrations of parthenolide (10, 20 and 30 mumol/L). [(3)H]thymidine incorporation was used as an index of cell proliferation. Cell cycle progression and distribution were determined by flow cytometric analysis. Furthermore, the expression of several regulatory proteins relevant to VSMC proliferation including IkappaBalpha, cyclooxygenase-2 (Cox-2), p21, and p27 was examined to investigate the potential molecular mechanism. Treatment with parthenolide significantly decreased the [(3)H]thymidine incorporation into DNA by 30%~56% relative to control values in a dose-dependent manner (P<0.05). Addition of parthenolide also increased cell population at G(0)/G(1) phase by 19.2%~65.7% (P<0.05) and decreased cell population at S phase by 50.7%~84.8% (P<0.05), which is consistent with its stimulatory effects on p21 and p27. In addition, parthenolide also increased IkappaBalpha expression and reduced Cox-2 expression in a time-dependent manner. Our results show that parthenolide significantly inhibits the VSMC proliferation by inducing G(0)/G(1) cell cycle arrest. IkappaBalpha and Cox-2 are likely involved in such inhibitory effect of parthenolide on VSMC proliferation. These findings warrant further investigation on potential therapeutic implications of parthenolide on VSMC proliferation in vivo.