Department of Gynecology, Shanghai First Maternity and Infant Hospital affiliated Tongji University, Shanghai 201204, China.
Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, United States.
Curr Cancer Drug Targets. 2018;18(7):677-696. doi: 10.2174/1568009617666170623114524.
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.
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.
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.
多药耐药性的最终出现仍然是癌症患者化疗治疗的严重限制。耐药性的最佳特征原因涉及 P-糖蛋白（Pgp）的过度表达，这会降低耐药性癌细胞中化学治疗剂的细胞内积累。因此，Pgp 已成为治疗化疗耐药性癌症的有吸引力的潜在靶标，但迄今为止，在临床试验中使用化疗联合 Pgp 抑制剂的结果令人失望。
我们在此检查 Pgp 与耐药性之间的关系，并更新通过靶向 Pgp 克服耐药性的策略，特别关注近年来在体外和体内靶向 Pgp 预防耐药性发展方面的最新进展。鉴于耐药性癌症模型在这些研究中的重要作用，还讨论了实验室中建立耐药性模型的常用方法。
考虑到 Pgp 在正常生理条件下的作用及其在解毒中的作用，目前可用的 Pgp 抑制剂在临床上无疑不能用于逆转耐药性。虽然靶向 Pgp 以预防和/或逆转耐药性的药物在临床试验中入组的癌症患者中使用时，其在实验室中使用的剂量没有益处，但靶向 Pgp 的化合物被广泛认为是规避耐药性的有前途的药物。
