Darbepoetin inhibits proliferation of hepatic cancer cells in the presence of TGF-β

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• 作者：Sabrina Ehnert (1) <br> Thomas Freude (1) <br> Carmen Eicher (2) <br> Britta Burkhardt (1) <br> Juan J. Martínez Sánchez (1) <br> Jan Neumann (3) <br> Ruben Mühl-Benninghaus (3) <br> Steven Dooley (4) <br> Stefan Pscherer (5) <br> Andreas K. Nussler (1) <br>
• 关键词：Hepatocytes ; Hepatoma cell lines ; TGF ; β1 ; Darbepoetin ; p53
• 刊名：Archives of Toxicology
• 出版年：2014
• 出版时间：January 2014
• 年：2014
• 卷：88
• 期：1
• 页码：89-96
• 全文大小：542 KB
• 作者单位：Sabrina Ehnert (1) <br> Thomas Freude (1) <br> Carmen Eicher (2) <br> Britta Burkhardt (1) <br> Juan J. Martínez Sánchez (1) <br> Jan Neumann (3) <br> Ruben Mühl-Benninghaus (3) <br> Steven Dooley (4) <br> Stefan Pscherer (5) <br> Andreas K. Nussler (1) <br><br>1. BG Trauma Center, Eberhard Karls Universit?t Tübingen, Schnarrenbergstra?e 95, 72076, Tübingen, Germany <br> 2. Department of Pediatric Surgery and Urology, Eberhard Karls Universit?t Tübingen, Hoppe-Seyler-Stra?e 1, 72076, Tübingen, Germany <br> 3. Department of Traumatology, Klinikum rechts der Isar, Technische Universit?t München, Ismaninger Stra?e 22, 81675, Munich, Germany <br> 4. Department of Medicine II, University Hospital Mannheim, Ruprecht-Karls-Universit?t Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany <br> 5. Department of Diabetology, Klinikum Traunstein, Cuno-Niggl-Stra?e 3, 83278, Traunstein, Germany <br>
• ISSN：1432-0738

文摘

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 (0-0?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-β1b> expression as compared to the other cell lines. Upon inhibition of TGF-β1b> signaling, DPO no longer reduced viability in Huh-7 cells. On the contrary, co-incubation with TGF-β1b> 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-β1b> supplementation. The knowledge of this mechanism offers great perspectives for the understanding and treatment of solid liver tumors.