Hepatology research : the official journal of the Japan Society of Hepatology · 2009
Fenretinide stimulates the apoptosis of hepatic stellate cells and ameliorates hepatic fibrosis in mice.
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Qian Jin, Zhang Jin Sheng, Wang Xue Qing, Ji Ju Ling, Mei Shuang
Аннотация
AIM: To investigate whether fenretinide, a clinically proved apoptosis-inducing chemopreventive agent in tumor cells, can induce apoptosis in hepatic stellate cells (HSCs) and resolve hepatic fibrosis.
METHODS: CCl(4)-induced liver fibrosis in mice and rat activated hepatic stellate cells (HSC-T6) as well as hepatocytes (BRL-3A) were studied.
RESULTS: The duplex staining of proliferating cell nuclear antigen and alpha- smooth muscle actin or terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling and alpha- smooth muscle actin demonstrated that fenretinide executed its anti-fibrosis effect in liver by inducing apoptosis rather than inhibiting proliferation of HSCs, while it had no apparently apoptotic effect on hepatocytes. Fenretinide could elicit apoptosis of HSC-T6 in vitro at the concentration range from 0.5 to 5 microM, but at higher concentrations >/=5 microM was required to induce apoptosis in hepatocytes (BRL-3A).
CONCLUSION: Further studies using malondialdehyde measurement, Western blot, antioxidant, inhibitors for p53, caspase 8 and 9 - as well as anti-Fas neutralizing antibody - have shown that in HSC-T6, fenretinide-induced apoptosis involves a reactive oxygen species (ROS)-generated, P53-independent, mitochondria-associated intrinsic pathway, whereas in hepatocytes (BRL-3A), a ROS-generated, P53-dependent, Fas-related extrinsic pathway is triggered only at high concentration.
METHODS: CCl(4)-induced liver fibrosis in mice and rat activated hepatic stellate cells (HSC-T6) as well as hepatocytes (BRL-3A) were studied.
RESULTS: The duplex staining of proliferating cell nuclear antigen and alpha- smooth muscle actin or terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling and alpha- smooth muscle actin demonstrated that fenretinide executed its anti-fibrosis effect in liver by inducing apoptosis rather than inhibiting proliferation of HSCs, while it had no apparently apoptotic effect on hepatocytes. Fenretinide could elicit apoptosis of HSC-T6 in vitro at the concentration range from 0.5 to 5 microM, but at higher concentrations >/=5 microM was required to induce apoptosis in hepatocytes (BRL-3A).
CONCLUSION: Further studies using malondialdehyde measurement, Western blot, antioxidant, inhibitors for p53, caspase 8 and 9 - as well as anti-Fas neutralizing antibody - have shown that in HSC-T6, fenretinide-induced apoptosis involves a reactive oxygen species (ROS)-generated, P53-independent, mitochondria-associated intrinsic pathway, whereas in hepatocytes (BRL-3A), a ROS-generated, P53-dependent, Fas-related extrinsic pathway is triggered only at high concentration.