Abstract
Background Sorafenib is an anticancer drug used in the treatment of unresectable hepatocellular carcinoma and advanced renal cell carcinoma. It is a substrate for the human OATP1B1. This study is aimed at assessing the role of OATP1B1 in transportation and uptake of sorafenib in hepatocellular carcinoma and how OATP1B1 affects the pharmacodynamics of sorafenib in vitro and in vivo. Methods Sorafenib transport was measured in HepG2, HepG2-OATP1B1∗1a, HepG2-OATP1B1∗1b, HepG2-OATP1B1∗15, LO2, LO2-OATP1B1∗1a, LO2-OATP1B1∗1b, and LO2-OATP1B1∗15 cells, as well as in HepG2 cells transfected with miR-148a mimics. The viability and apoptosis rate of cells treated with sorafenib were evaluated. A liver cancer rat model was established to explore the pharmacokinetics and pharmacodynamics of sorafenib after overexpression of Oatp2. Results Changes in expression and genetic mutations of OATP1B1 significantly affected the uptake of sorafenib in HepG2 and LO2 transgenic cells, and the uptake of sorafenib was higher in HepG2 than LO2. Genetic mutations of OATP1B1 significantly affected the cell viability and apoptosis rate of HepG2 cells after sorafenib treatment. Compared to control group, the uptake of sorafenib in miR-148a mimic-transfected HepG2 cells was decreased, and the cell viability was increased. PCN significantly increased the expression of Oatp2 and affected the pharmacokinetics of sorafenib. Vascular endothelial growth factor levels and microvascular density in tumor-adjacent tissues decreased significantly, suggesting that increased Oatp2 expression improves the treatment effect of sorafenib in a rat model of liver cancer. Conclusions OATP1B1 plays an important role in the pharmacokinetics and pharmacodynamics of sorafenib in hepatocellular carcinoma.
Highlights
Sorafenib is an anticancer drug used in the treatment of unresectable hepatocellular carcinoma and advanced renal cell carcinoma
Polymorphisms of organic anion transport polypeptide 1B1 (OATP1B1) significantly affected the treatment effect of sorafenib in hepatocellular carcinoma, consistent with the notion that certain reduced function variants of SLCO1B1 were associated with an increased risk of sorafenib-associated toxicity [11]. These results suggest that OATP1B1 may play an important role in pharmacodynamics of sorafenib
OATP1B1 plays an important role in the pharmacokinetics and pharmacodynamics of sorafenib
Summary
Sorafenib is an anticancer drug used in the treatment of unresectable hepatocellular carcinoma and advanced renal cell carcinoma. OATP1B1 ( known as OATP-C or LST-1 and coded by the gene SLCO1B1) is an uptake transporter expressed in the basolateral (sinusoidal) membrane of hepatocytes and plays an important role in the transport of endogenous substances and a variety of clinical drugs [4]. It has 2 single nucleotide polymorphisms: 388 A > G (63% mutation frequency in Asian populations) and 521 T > C (16% mutation frequency in Asian populations) [5], which form four haplotypes: OATP1B1∗1a It has 2 single nucleotide polymorphisms: 388 A > G (63% mutation frequency in Asian populations) and 521 T > C (16% mutation frequency in Asian populations) [5], which form four haplotypes: OATP1B1∗1a (c.388APc.521 T), OATP1B1∗1b (c.388GPc.521 T), OABP1B1∗5 (c.388APc.521 C), and OATP1B1∗15
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