Enhanced antitumour drug delivery to cholangiocarcinoma through the apical sodium-dependent bile acid transporter (ASBT).
Novel antitumour drugs, such as cationic tyrosine kinase inhibitors, are useful in many types of cancer but not in others, such as cholangiocarcinoma (CCA), where their uptake through specific membrane transporters, such as OCT1, is very poor. Here we have investigated the usefulness of targeting cytostatic bile acid derivatives to enhance the delivery of chemotherapy to tumours expressing the bile acid transporter ASBT and whether this is the case for CCA. The analysis of paired samples of CCA and adjacent non-tumour tissue collected from human (n=15) and rat (n=29) CCA revealed that ASBT expression was preserved. Moreover, ASBT was expressed, although at different levels, in human and rat CCA cell lines. Both cells in vitro and rat tumours in vivo were able to carry out efficient uptake of bile acid derivatives. Using Bamet-UD2 (cisplatin-ursodeoxycholate conjugate) as a model ASBT-targeted drug, in vitro and in vivo antiproliferative activity was evaluated. ASBT expression enhanced the sensitivity to Bamet-UD2, but not to cisplatin, in vitro. In nude mice, Bamet-UD2 (more than cisplatin) inhibited the growth of human colon adenocarcinoma tumours with induced stable expression of ASBT. As compared with cisplatin, administration of Bamet-UD2 to rats with CCA resulted in an efficient liver and tumour uptake but low exposure of extrahepatic tissues to the drug. Consequently, signs of liver/renal toxicity were absent in animals treated with Bamet-UD2. In conclusion, endogenous or induced ASBT expression may be useful in pharmacological strategies to treat enterohepatic tumours based on the use of cytostatic bile acid derivatives.
Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, IBSAL, Salamanca, Spain.
Elisa
E
Lozano
Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain.
Maria J
MJ
Monte
Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain.
Oscar
O
Briz
Department of Biochemistry and Molecular Biology, University of Salamanca, IBSAL, Salamanca, Spain.
Angel
A
Hernández-Hernández
Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), Ikerbasque, San Sebastián, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain.
Jesus M
JM
Banales
Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain. Electronic address: jjgmarin@usal.es.
Jose J G
JJ
Marin
Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, IBSAL, Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain.
Rocio I R
RI
Macias
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use*; D001650:Bile Duct Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018281:Cholangiocarcinoma / Q000188:drug therapy*; D002945:Cisplatin / Q000008:administration & dosage / Q000627:therapeutic use; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D029363:Organic Anion Transporters, Sodium-Dependent / Q000187:drug effects / Q000378:metabolism*; D009944:Organoplatinum Compounds; D051381:Rats; D017208:Rats, Wistar; D027981:Symporters / Q000187:drug effects / Q000378:metabolism*; D014580:Ursodeoxycholic Acid / Q000737:chemistry
D000970:Antineoplastic Agents; C416424:Bamet-UD2; D029363:Organic Anion Transporters, Sodium-Dependent; D009944:Organoplatinum Compounds; D027981:Symporters; C071908:sodium-bile acid cotransporter; D014580:Ursodeoxycholic Acid; D002945:Cisplatin
Biliary tumour; Cancer; Chemoresistance; Chemotherapy; Cisplatin; Drug targeting; Ursodeoxycholic acid