Liver-on-a-chip platform to study anticancer effect of statin and its metabolites
Liver-on-a-chip platform to study anticancer effect of statin and its metabolites
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DOI：
10.1016/j.bej.2020.107831
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发表时间：
2021-01-15
影响因子：
3.9
通讯作者：
Hou, Yung-Te
中科院分区：
文献类型：
--
作者：
Chen, Pin-Yao;Hsieh, Meng-Ju;Hou, Yung-Te
癌症是全球主要的死亡原因，但抗癌药物可能会导致特殊的肝脏损伤。由于肝脏是参与药物代谢最活跃的器官，也是生物转化的主要部位，我们应用肝脏组织工程和微流控技术开发了肝脏毒性传感器平台。我们还在体外验证了他汀类药物及其活性代谢产物对癌细胞的作用。结果表明，与传统培养皿相比，芯片上肝细胞内白蛋白和尿素的合成率分别提高了10倍和4倍，白蛋白、细胞色素P1A1、细胞色素P1A2、细胞色素P3A23和细胞色素P3A4的表达分别增加了4.6、3.4、13.8、10.7和3.4倍，表明该芯片肝细胞具有促进肝功能的作用。辛伐他汀(HMS)的活性代谢产物来源于肝细胞代谢，可明显降低人前列腺癌和肝癌细胞的存活率，而对原代肝细胞和成纤维细胞等正常细胞无明显毒性。LOC不仅可以准确地反映真实的肝脏内环境，还可以作为体外药物代谢和毒物研究的平台。该LOC可能在不久的将来成为抗癌药物筛选的公认平台。
Cancer is a leading cause of death worldwide, but anticancer drugs may cause idiosyncratic liver injury. Because the liver is the organ most actively involved in drug metabolism and the primary site for biotransformation, we developed a hepatotoxicity sensor platform by applying liver tissue engineering and microfluidic techniques. We also validated the effect of statin and its active metabolites on cancer cells in vitro. The results revealed that compared with those in a traditional culture dish, the rates of albumin and urea syntheses in hepatocytes on a liver-on-a-chip (LOC) were ten and four times higher, respectively, and albumin, CYP1A1, CYP1A2, CYP3A23 and CYP3A4 expression was 4.6, 3.4, 13.8, 10.7 and 3.4 times higher, respectively; that is, hepatic functions could be promoted on this LOC. The active metabolites of simvastatin (HMS) derived from hepatocellular metabolism evidently reduced the viability of human prostatic cancer and liver cancer cells without exhibiting significant toxicity to normal cells such as primary hepatocytes and fibroblasts. The LOC can not only accurately represent an actual internal liver environment but also serve as an in vitro drug metabolism and toxicant research platform. This LOC may become an accepted platform for anticancer drug screening in the near future.