Inhibition of hepatic stellate cell proliferation and activation by the semisynthetic analogue of fumagillin TNP-470 in rats

Proliferation and activation of hepatic stellate cells (HSCs) are critical steps for the development of postnecrotic fibrosis in the liver. The presen t study aimed to reveal the inhibitory effect of the semisynthetic analogue of fumagillin TNP-470 on these events for its possible use as an antifibro genic agent. Rat models of carbon tetrachloride (CCl4)- and dimethylnitrosa mine-induced hepatic fibrosis were used for an in vivo study. In both model s, the fibrotic area was considerably decreased by concurrent repetitive su bcutaneous injections of 30 mg/kg body weight of TNP-470. In CCl4-induced f ibrosis, factor VIII-related antigen-positive blood vessels, desmin-, or al pha -smooth muscle actin (alpha SMA)-positive mesenchymal cells, bromodeoxy uridine (BrdU)-positive mesenchymal cells also decreased in number by treat ment with TNP-470. In in vitro experiments, a supplement of 1,000 ng/mL TNP -470 suppressed BrdU incorporation and cyclins D1, D2, and E expression by cultured HSCs in the absence and/or presence of platelet-derived growth fac tor (PDGF). Expression of HSC activation markers, i.e,, alpha SMA and PDGF receptor beta, was also suppressed. The present results indicate that TNP-4 70 inhibits HSC proliferation by blocking the cell-cycle transition from G1 to S and HSC activation, and, as the consequence, prevents the progression of hepatic fibrosis, probably being coupled with its antiangiogenic effect .