Maraviroc, a CCR5 Antagonist, Prevents Development of Hepatocellular Carcinoma in a Mouse Model

被引:76
|
作者
Ochoa-Callejero, Laura [1 ]
Perez-Martinez, Laura [2 ]
Rubio-Mediavilla, Susana [3 ]
Oteo, Jose A. [2 ]
Martinez, Alfredo [1 ]
Blanco, Jose R. [2 ]
机构
[1] Ctr Biomed Res La Rioja CIBIR, Oncol Area, Logrono, Spain
[2] Ctr Biomed Res La Rioja CIBIR, Infect Dis Area, Logrono, Spain
[3] Hosp San Pedro, Pathol Serv, Logrono, Spain
来源
PLOS ONE | 2013年 / 8卷 / 01期
关键词
HEPATIC STELLATE CELLS; CHEMOKINE RECEPTOR 5; CHOLINE-DEFICIENT; LIVER INFLAMMATION; OVAL CELLS; CANCER; MIGRATION; PROMOTES; INJURY; PROLIFERATION;
D O I
10.1371/journal.pone.0053992
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Chronic liver disease may result in a sequential progression through fibrosis, cirrhosis and lead, eventually, to hepatocellular carcinoma (HCC). Hepatic stellate cells (HSC) seem to be responsible for the fibrogenic response through the activation of an autocrine loop involving the chemokine receptor, CCR5. However, the role of CCR5 in HCC remains poorly understood. Since this receptor is also one of the main ports of entry for the human immunodeficiency virus (HIV), several CCR5 inhibitors are being used in the clinic to reduce viral load. We used one of these inhibitors, maraviroc (MVC), in a mouse model of diet-induced HCC to investigate whether this intervention would reduce disease progression. Animals treated with MVC on top of a normal control diet did not present any evidence of toxicity or any morphological change when compared with non-treated mice. Animals treated with MVC presented higher survival, less liver fibrosis, lower levels of liver injury markers and chemokines, less apoptosis, lower proliferation index, and lower tumor burden than their counterparts receiving only the hepatotoxic diet. In addition, MVC inhibits HSC activation markers such as phosphorylation of p38 and ERK, and increases hepatocyte survival. This study suggests that MVC, a well tolerated and clinically characterized drug, may be used as a preventative treatment for HCC. Clinical studies are needed to demonstrate the efficacy of this drug, or other CCR5 inhibitors, in patients with high risk of developing HCC.
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页数:13
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