Molecular bases of liver cancer refractoriness to pharmacological treatment.
Hepatocellular carcinoma and cholangiocarcinoma are the two most important primary malignancies of the liver. These are among the tumours with the lowest response to pharmacological treatment based on currently available drugs. This is due either to the existence of refractoriness of the initial tumour or to the ability of cancer cells to develop chemoresistance during treatment. Liver cancers share some of the mechanisms responsible for drug refractoriness with other types of tumours, such as a reduction in drug uptake; enhanced drug export; intracellular inactivation of the active agent; alteration of the molecular target; an increase in the activity of the target route to be inhibited, or the appearance or stimulation of alternative routes; enhanced repair of drug-induced modifications in the target molecules, and the activation/ inhibition of intracellular signalling pathways, all of which lead to a negative balance between the apoptosis/survival of tumour cells. The aim of the present article is to review how these mechanisms of chemoresistance affect the different families of drugs that are being or have been used to treat hepatocellular carcinoma and cholangiocarcinoma. A better understanding of the molecular bases of drug refractoriness is needed in order to develop novel drugs or pharmacological strategies aimed at overcoming resistance to anticancer agents.
Marin
J J G
JJ
Laboratory of Experimental Hepatology and Drug Targeting, University Hospital of Salamanca, Biomedical Research Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), University of Salamanca, Salamanca, Spain. jjgmarin@usal.es
Romero
M R
MR
Briz
O
O
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D018943:Anthracyclines / Q000737:chemistry / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D056831:Coordination Complexes / Q000737:chemistry / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D011034:Podophyllotoxin / Q000737:chemistry / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000627:therapeutic use; D011743:Pyrimidines / Q000737:chemistry / Q000627:therapeutic use
D018528:ATP-Binding Cassette Transporters; D018943:Anthracyclines; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D056831:Coordination Complexes; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011034:Podophyllotoxin