Selective apoptosis in hepatic stellate cells mediates the antifibrotic effect of phenanthrenes from Dendrobium nobile

Abstract

Regardless of the etiology, cellular death of the liver parenchymal hepatocyte seems to be a primary event of hepatic fibrogenesis, which ultimately results in hepatic stellate cell (HSC) activation and the synthesis of extracellular matrix proteins. Recently it has been demonstrated that hepatic fibrosis can be a reversible process when the stimulus is properly eliminated. Apoptotic removal of active HSC is considered an essential part of the resolution. By employing the HSC cell line, HSC-T6, it was found that the methanol extract of Dendrobium nobile stem significantly inhibited the proliferation of HSC-T6 cells. Three phenanthrenes, denbinobin, fimbriol B and 2,3,5-trihydroxy-4,9-dimethoxyphenanthrene isolated from D. nobile were proven to inhibit HSC proliferation. Growth arrest of HSCs by these compounds was accompanied by cellular loss via autophagy-linked apoptosis. The maximal dose of these compounds, however, had little effect on primary cultured hepatocytes in rats. Collagen deposition in HSC-T6 cells was attenuated by these phenanthrenes. Collectively, the above results demonstrated that denbinobin, fimbriol B and 2,3,5-trihydroxy-4,9-dimethoxyphenanthrene exhibited antifibrotic activities possibly by the induction of selective cell death in HSCs but not in hepatocytes, implying that these compounds may be useful candidates for developing therapeutic agents for the prevention and treatment of hepatic fibrosis.