Liver-on-a-chip platform to study anticancer effect of statin and its metabolites

Abstract

• A liver-on-chip platform was developed for determining the effect of statin and its metabolites on cancer cell. • The hepatic functions and gene expression levelof hepatocytes in liver-on-chip platform were better than that in general culture dish. • The active metabolites of Simvastatin converted by hepatic enzymesare toxic to PC3 and HepG2. • The active metabolites of Atorvastatinconverted by hepatic enzymesare non-toxic to PC3 and HepG2. 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.