Figure 1.

There are five mechanisms on how tumor cells acquire drug resistance. Firstly, reduction of drug uptake by increased efflux and decreased influx of chemotherapeutics through ABC transporters and solute carrier proteins, respectively. Secondly, alteration of the drug targets, for instance by decreasing protein expression of DNA topoisomerase, an important target of doxorubicin, which is responsible for inducing DNA strand breaks during doxorubicin treatment. Thirdly, by induction of drug-detoxifying mechanisms, such as scavenging of reactive oxygen species (ROS) or by nucleophilic conjugation of glutathione to the active site of chemotherapeutics, which is mediated by glutathione transferase enzymes. Fourthly, by repairing drug-induced damages, such as DNA damage, which can be directly induced by chemotherapeutics or through oxidative stress. Lastly, by inducing insensitivity to cell death through activation of several pathways, including NFkB, STAT3, and Nrf2. These five molecular mechanisms are heavily intertwined, thereby often accelerating the drug-resistant phenotype of hepatocellular carcinoma.