Abstract
The development of multidrug resistance (MDR) is one of the major challenges to the success of traditional chemotherapy treatment in cancer patients. Most studies to date have focused on strategies to reverse MDR following its development. However, agents utilizing this approach have proven to be of limited clinical use, failing to demonstrate an improvement in therapeutic efficacy with almost no significant survival benefits observed in cancer clinical trials. An alternative approach that has been applied is to prevent or delay MDR prior or early in its development. Recent investigations have shown that preventing the emergence of MDR at the onset of chemotherapy treatment, rather than reversing MDR once it has developed, may assist in overcoming drug resistance. In this review, we focus on a number of novel strategies used by small-molecule inhibitors to prevent the development of MDR. These agents hold great promise for prolonging the efficacy of chemotherapy treatment and improving the clinical outcomes of patients with cancers that are susceptible to MDR development.
Highlights
Multidrug resistance (MDR) is a phenomenon by which, after exposure to a chemotherapeutic agent, cancer cells develop resistance, and simultaneous cross-resistance, to a wide range of functionally and structurally unrelated chemotherapeutic drugs [1, 2]
Experimental drug resistance cancer models have contributed to the identification of many of the underlying mechanisms involved in the development of multidrug resistance (MDR)
Recent studies have demonstrated that several small-molecule inhibitors, including Pgp inhibitors, are capable at preventing the development of MDR when co-treated with cytotoxic drugs in different in vitro and in vivo model systems (Table 1)
Summary
Multidrug resistance (MDR) is a phenomenon by which, after exposure to a chemotherapeutic agent, cancer cells develop resistance, and simultaneous cross-resistance, to a wide range of functionally and structurally unrelated chemotherapeutic drugs [1, 2]. In order to investigate strategies for the prevention of MDR in human cancer, it is necessary to establish a model of the process in which resistance develops after exposure of sensitive tumor cells to chemotherapeutic drugs.
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