Drug metabolizing enzymes and their inhibitors' role in cancer resistance

Despite continuous research on chemotherapeutic agents, different mechanisms of resistance have become a major pitfall in cancer chemotherapy. Although, exhaustive efforts are being made by several researchers to target resistance against chemotherapeutic agents, there is another class of resistance mechanism which is almost carrying on unattended. This class of resistance includes pharmacokinetics resistance such as efflux by ABC transporters and drug metabolizing enzymes. ABC transporters are the membrane bound proteins which are responsible for the movement of substrates through the cell membrane. Drug metabolizing enzymes are an integral part of phase-II metabolism that helps in the detoxification of exogenous, endogenous and xenobiotics substrates. These include uridine diphospho-glucuronosyltransferases (UGTs), glutathione-S-transferases (GSTs), dihydropyrimidine dehydrogenases (DPDs) and thiopurine methyltransferases (TPMTs). These enzymes may affect the role of drugs in both positive as well negative manner, depending upon the type of tissue and cells present and when present in tumors, can result in drug resistance. However, the underlying mechanism of resistance by drug metabolizing enzymes is still not clear. Here, we have tried to cover various aspects of these enzymes in relation to anticancer drugs.