Combined action and regulation of phase II enzymes and multidrug resistance proteins in multidrug resistance in cancer

A major limitation in the treatment of cancer patients is the ability of cancer cells to become resistant to chemotherapeutic drugs, a phenomenon known as multidrug resistance (MDR). Two important mechanisms involved in multidrug resistance are the increased activity of efflux pumps, such as those of the multidrug resistance proteins (MRPs) and the detoxification by phase II conjugating enzymes, like glutathione S-transferases and UDP-glucuronosyltransferases. A synergistic interaction between these two mechanisms, MRPs and phase II enzymes, in conferring MDR has been shown for multiple anticancer drugs. In addition, there is substantial evidence of a coordinate regulation of the expression of phase II enzymes and MRPs, most likely mediated by the nuclear factor-erythroid 2 p45-related factor (Nrf2) and antioxidant response elements. Further elucidation of the combined action and regulation of phase II enzymes and MRPs in MDR will be an aid in the improvement of the chemotherapeutic treatment of cancer patients. (C) 2008 Elsevier Ltd. All rights reserved.