Relevance of the organic anion transporting polypeptide 1B3 (OATP1B3) in the personalized pharmacological treatment of hepatocellular carcinoma

• Published in: Biochemical pharmacology 2023-08, Vol.214, p.115681-115681, Article 115681
• Main Authors: Asensio, Maitane, Herraez, Elisa, Macias, Rocio I.R., Lozano, Elisa, Muñoz-Bellvís, Luis, Sanchez-Vicente, Laura, Morente-Carrasco, Ana, Marin, Jose J.G., Briz, Oscar
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Chemoresistance; Cisplatin - metabolism; Drug transport; Humans; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Mice; Organic Anion Transporters - metabolism; Organic Anion Transporters, Sodium-Independent - metabolism; Solute Carrier Organic Anion Transporter Family Member 1B3 - genetics; Targeted therapy; Tyrosine kinase inhibitors
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2023.115681

[Display omitted] Although pharmacological treatment is the best option for most patients with advanced hepatocellular carcinoma (HCC), its success is very limited, partly due to reduced uptake and enhanced efflux of antitumor drugs. Here we have explored the usefulness of vectorizing drugs towards the organic anion transporting polypeptide 1B3 (OATP1B3) to enhance their efficacy against HCC cells. In silico studies (RNA-Seq data, 11 cohorts) and immunohistochemistry analyses revealed a marked interindividual variability, together with general downregulation but still expression of OATP1B3 in the plasma membrane of HCC cells. The measurement of mRNA variants in 20 HCC samples showed the almost absence of the cancer-type variant (Ct-OATP1B3) together with marked predominance of the liver-type variant (Lt-OATP1B3). In Lt-OATP1B3-expressing cells, the screening of 37 chemotherapeutical drugs and 17 tyrosine kinase receptors inhibitors (TKIs) revealed that 10 classical anticancer drugs and 12 TKIs were able to inhibit Lt-OATP1B3-mediated transport. Lt-OATP1B3-expressing cells were more sensitive than Mock parental cells (transduced with empty lentiviral vectors) to some Lt-OATP1B3 substrates (paclitaxel and the bile acid-cisplatin derivative Bamet-UD2), but not to cisplatin, which is not transported by Lt-OATP1B3. This enhanced response was abolished by competition with taurocholic acid, a known Lt-OATP1B3 substrate. Tumors subcutaneously generated in immunodeficient mice by Lt-OATP1B3-expressing HCC cells were more sensitive to Bamet-UD2 than those derived from Mock cells. In conclusion, Lt-OATP1B3 expression should be screened before deciding the use of anticancer drugs substrates of this carrier in the personalized treatment of HCC. Moreover, Lt-OATP1B3-mediated uptake must be considered when designing novel anti-HCC targeted drugs.