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Title
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Therapeutic effects of artesunate in hepatocellular carcinoma: repurposing an ancient antimalarial agent
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Author
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Abstract
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| Objectives Artemisinins are antimalarial drugs that exert potent anticancer activity. We evaluated the effects of artesunate, a semisynthetic derivative of artemisinin, on tumor growth, angiogenesis, the unfolded protein response, and chemoresistance in hepatocellular carcinoma. Materials and methods The effect of artesunate was examined in HepG2 and BWTG3 cells under normoxic and hypoxic conditions and in a diethylnitrosamine-induced mouse model. Histology was performed with hematoxylin/eosin and reticulin staining. The expression of chemoresistance-related transporters and angiogenic and unfolded protein response factors was determined. Cytotoxicity was assessed by alanine and aspartate transaminase, lactate dehydrogenase, water-soluble tetrazolium salt, and caspase-3 activity assays. Small animal imaging was performed using dynamic contrast-enhanced MRI and choline PET to assess tumor progression. Results Artesunate dose dependently reduced cell viability (from 50 mu mol/l; P < 0.05) and increased caspase-3 activity (P < 0.05) in HepG2 and BWTG3 cells. These effects were enhanced by hypoxia (from 12.5 mu mol/l; P < 0.01). Moreover, artesunate downregulated vascular endothelial growth factor and placental growth factor expression in vitro (both P < 0.05) and in vivo (both P < 0.01). In mice, artesunate decreased vessel density and tumor burden (both P < 0.05). These in-vivo effects were enhanced by combination with sorafenib (P < 0.05 and P = 0.07, respectively), without apparent hepatotoxicity. Furthermore, artesunate modulated the unfolded protein response in vitro and in vivo, increasing proapoptotic signaling, and did not induce doxorubicin chemoresistance. Conclusion These findings indicate that artesunate could offer a new approach to the therapy of hepatocellular carcinoma. Clinical trials with artesunate as monotherapy or in combination with current hypoxia-inducing approaches are necessary. Eur J Gastroenterol Hepatol 26: 861-870 (C) 2014 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. |
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Language
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English
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Source (journal)
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European journal of gastroenterology & hepatology. - Melville, N.Y.
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Publication
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Melville, N.Y.
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2014
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ISSN
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0954-691X
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DOI
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10.1097/MEG.0000000000000066
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Volume/pages
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26
:8
(2014)
, p. 861-870
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ISI
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000338722300006
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Pubmed ID
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24987823
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Full text (Publisher's DOI)
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