Cancer type­SLCO1B3 promotes epithelial­mesenchymal transition resulting in the tumour progression of non­small cell lung cancer.

Non­small cell lung cancer (NSCLC) is one of the most common histologically defined subtypes of lung cancer. To identify a promising molecular target for NSCLC therapy, we performed gene expression analysis at the exon level using postoperative specimens of NSCLC patients. Exon array and real­time PCR analyses revealed that an alternative splicing variant of solute carrier organic anion transporter family member 1B3 (SLCO1B3) called cancer type­SLCO1B3 (Ct­SLCO1B3) was significantly upregulated in the NSCLC samples. SLCO1B3 expressed in the liver [liver type (Lt)­SLCO1B3] was found to be localised in the cell membrane, whereas Ct­SLCO1B3 was detected in the cytoplasm of NSCLC cells. RNAi­mediated knockdown of Ct­SLCO1B3 inhibited in vitro anchorage­independent cell growth, cell migration, and in vivo tumour growth of A549 cells. Overexpression of Ct­SLCO1B3 but not Lt­SLCO1B3 upregulated anchorage­independent cell growth and cell migration of NCI­H23 cells. Mechanistically, Ct­SLCO1B3 was found to regulate the expression of epithelial­mesenchymal transition (EMT)­related genes. The upregulation of E­cadherin was discovered to be especially pivotal to phenotypes of Ct­SLCO1B3­suppressed A549 cells. These findings suggest that Ct­SLCO1B3 functions as a tumour­promoting factor via regulating EMT­related factors in NSCLC.

[Quantitative assessment of the risk of OATP1B1/1B3-mediated drug-drug interactions].

Drug transporters play important roles in determining drug pharmacokinetics. Organic anion transporting polypeptides 1B1/1B3 (OATP1B1/1B3) are transporters mediating hepatic uptake of various anionic drugs. OATP1B1/1B3 activities are changed by genetic mutation and drug-drug interaction (DDI) that could lead to severe adverse reactions. Methods to address the precise DDI risk assessment have been developed in addition to the translational assessment from the results of in vitro studies. Using endogenous substrates as probes is an emerging approach that allows clinical assessment of the DDI risk in the early phase of drug development. Then, the clinical data will be subjected to the pharmacokinetic analysis using physiologically-based pharmacokinetic models to perform the more realistic DDI risk assessment with OATP1B1/1B3 substrate drugs. When drug targets are located inside the hepatocytes, DDI impact on the intrahepatic concentration is critical for their pharmacological actions. Positron emission tomography (PET) allows researchers to determine tissue concentration time profiles of the PET probe upon the inhibition of OATP1B1/1B3, and to estimate the change in kinetic parameter for each intrinsic process of hepatic elimination of PET probe. Integration of the clinical data into the PBPK model realizes more precise prediction of DDI impact on the pharmacokinetics of drugs, and their therapeutic effects.

Organic anion transport polypeptide 1b2 selectively affects the pharmacokinetic interaction between paclitaxel and sorafenib in rats.

Paclitaxel, a broad-spectrum antitumor drug, is widely used as a cytotoxic drug, while sorafenib as a multi-kinase inhibitor is a classic targeted drug. A number of clinical trials have combined paclitaxel and sorafenib for cancer treatment, with the expectation of better therapeutic effects. However, the toxicity and side effects in the treatment are significantly increased. In this report, the organic anion transport polypeptide 1b2 (Oatp1b2) overexpression cell model and the Oatp1b2 knockout (KO) rat model were used to investigate the drug-drug interactions (DDI) between paclitaxel and sorafenib. In Oatp1b2-overexpressed cells, sorafenib inhibited the uptake of paclitaxel in a concentration-dependent manner. In wild-type (WT) rats, sorafenib increased the systemic exposure and slowed the elimination of paclitaxel, resulting in DDI. In Oatp1b2 KO rats, however, the DDI disappeared. Interestingly, paclitaxel did not alter the pharmacokinetic profiles of sorafenib. Further studies found that sorafenib was not the substrate of Oatp1b2 in rats. In general, the combination of paclitaxel and sorafenib caused Oatp1b2-mediated DDI in vitro and in vivo, because sorafenib inhibited Oatp1b2 activity and affected the pharmacokinetic properties of paclitaxel. This study may provide useful information for understanding the role of OATP1B in paclitaxel-sorafenib interaction.