Background: The ultimate emergence of multidrug resistance remains a severe limitation
of chemotherapy treatment for patients with cancer. The best-characterized cause of drug resistance
involves the overexpression of P-glycoprotein (Pgp), which decreases the intracellular accumulation
of chemotherapeutic agents in drug-resistant cancer cells. Thus, Pgp has become an attractive potential
target for treating chemotherapy-resistant cancer, but the outcomes of using chemotherapy in
combination with Pgp inhibitors in clinical trials to date have been disappointing.
Objective: We herein examine the relationship between Pgp and drug resistance and update the
strategies for overcoming drug resistance by targeting Pgp, with a special focus on the recent progress
in the area of preventing the development of drug resistance by targeting Pgp both in vitro and
in vivo. Given the essential roles of drug-resistant cancer models in these investigations, commonly
used approaches for establishing drug-resistant models in the laboratory are also addressed.
Conclusion: Considering the roles of Pgp in normal physiological conditions and its appreciated
roles in detoxification, the currently available Pgp inhibitors undoubtedly cannot be used to reverse
drug resistance in the clinic. Although agents that target Pgp to prevent and/or reverse drug resistance
are not beneficial at the doses used in the laboratory when administered to patients with cancer
who are enrolled in clinical trials, compounds targeting Pgp are widely acknowledged to be promising
for circumventing drug resistance.