RESUMEN
An important factor determining the pharmacological response to antitumor drugs is their concentrations in cancer cells, which accounts for the net interaction with their intracellular molecular targets. Accordingly, mechanisms leading to reduced intracellular levels of active agents play a crucial role in cancer chemoresistance. These include impaired drug uptake through solute carrier (SLC) proteins and efficient drug export by ATP-dependent pumps belonging to the ATP-binding cassette (ABC) superfamily of proteins. Since the net movement of drugs in-and-out the cells depends on the overall expression of carrier proteins, defining the so-called transportome, special attention has been devoted to the study of transcriptome regarding these proteins. Nevertheless, genetic variants affecting SLC and ABC genes may markedly affect the bioavailability and, hence, the efficacy of anticancer drugs.
Asunto(s)
Carcinoma Hepatocelular/genética , Enfermedades del Sistema Digestivo/genética , Neoplasias Hepáticas/genética , Transportadoras de Casetes de Unión a ATP/genética , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Transporte Biológico/efectos de los fármacos , Transporte Biológico/genética , Carcinoma Hepatocelular/tratamiento farmacológico , Enfermedades del Sistema Digestivo/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Farmacogenética/métodosRESUMEN
Primary liver cancers constitute the fourth most deadly group of cancers. Their poor prognosis is due in part to the pre-existence and/or development, often during treatment, of powerful mechanisms accounting for the poor response of cancer cells to antitumor drugs. These include both impaired gene expression and the appearance of spliced variants, polymorphisms and mutations, affecting the function of genes leading to the reduction in intracellular concentrations of active agents, changes in molecular targets and survival pathways, altered tumor microenvironment and phenotypic transition. The present review summarizes available information regarding the role of germline and somatic mutations affecting drug transporters, enzymes involved in drug metabolism, organelles and signaling molecules related to liver cancer chemoresistance. A more complete picture of the actual complexity of this problem is urgently needed for carrying out further pharmacogenomic studies aimed to improve the management of patients suffering from hepatocellular carcinoma or cholangiocarcinoma.
