Abstract：
:Darbepoetin (DPO), an erythropoietin (EPO) derivative, was licensed in 2002 to treat patients with solid tumors suffering from chemotherapy-dependent anemia, although various tumors express EPO to improve vascularization, thus favoring tumor growth and spreading. Therefore, we wanted to investigate direct effects of DPO on the liver tumor cell lines HepG2, SkHep1, Huh-7, AKN1, HCC-T and HCC-M, as well as on primary human hepatocytes (hHeps). DPO (0-40 ng/ml) did not affect viability of hHeps, HepG2, SkHep1, AKN1, HCC-T and HCC-M cells, as determined by Resazurin conversion. However, Huh-7 cells' viability dose-dependently decreased from 5 ng/ml DPO on. Lack of LDH release into culture medium and negative DNA laddering excluded apoptosis or necrosis as the cause for the reduced Resazurin conversion. In Huh-7 cells, DPO increased the expression of p53. Interestingly, Huh-7 cells showed the highest basal TGF-β1 expression as compared to the other cell lines. Upon inhibition of TGF-β1 signaling, DPO no longer reduced viability in Huh-7 cells. On the contrary, co-incubation with TGF-β1 made the other cell lines responsive to DPO. Summarizing our data, we show that DPO reduces the growth of Huh-7 cells by up-regulation of the tumor-suppressor gene p53. This mechanism seems to be dependent on a strong TGF-β expression and corresponding signaling in these cells, as other cell lines became responsive to DPO with TGF-β1 supplementation. The knowledge of this mechanism offers great perspectives for the understanding and treatment of solid liver tumors.
journal_name
Arch Toxicoljournal_title
Archives of toxicologyauthors
Ehnert S,Freude T,Eicher C,Burkhardt B,Martínez Sánchez JJ,Neumann J,Mühl-Benninghaus R,Dooley S,Pscherer S,Nussler AKdoi
10.1007/s00204-013-1094-5subject
Has Abstractpub_date
2014-01-01 00:00:00pages
89-96issue
1eissn
0340-5761issn
1432-0738journal_volume
88pub_type
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