Bidwell Gene L, Davis Aisha N, Fokt Izabela, Priebe Waldemar, Raucher Drazen
Department of Biochemistry, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA.
Invest New Drugs. 2007 Aug;25(4):313-26. doi: 10.1007/s10637-007-9053-8. Epub 2007 May 5.
The ability of cancer cells to become simultaneously resistant to different drugs, a trait known as multidrug resistance, remains a major obstacle for successful anticancer therapy. One major mechanism of resistance involves cellular drug efflux by expression of P-glycoprotein (P-gp), a membrane transporter with a wide variety of substrates. Anthracyclines are especially prone to induction of resistance by the P-gp mechanism. P-gp mediated resistance is often confronted by use of P-gp inhibitors, synthesis of novel analogs, or conjugating drugs to macromolecular carriers in order to circumvent the efflux mechanism. In this report, the effect of free and Elastin-like polypeptide (ELP) bound doxorubicin (Dox) on the viability of sensitive (MES-SA and MCF-7) and multidrug resistant (MES-SA/Dx5 and NCI/ADR-RES) human carcinoma cells was studied in vitro. The resistant MES-SA/Dx5 cells demonstrated about 70 times higher resistance to free Dox than the sensitive MES-SA cells, and the NCI/ADR-RES cells were about 30 fold more resistant than the MCF-7 cells. However, the ELP-bound Dox was equally cytotoxic in both sensitive and resistant cell lines. The ELP-bound Dox was shown to accumulate in MES-SA/Dx5 cells, as opposed to free Dox, which was rapidly pumped out by the P-gp transporter. Since ELP is a thermally responsive carrier, the effect of hyperthermia on the cytotoxicity of the ELP-Dox conjugate was investigated. Both cytotoxicity and apoptosis were enhanced by hyperthermia in the Dox resistant cells. The results suggest that ELP-Dox conjugates may provide a means to thermally target solid tumors and to overcome drug resistance in cancer cells.
癌细胞同时对不同药物产生抗性的能力，即所谓的多药耐药性，仍然是成功进行抗癌治疗的主要障碍。一种主要的耐药机制涉及通过P-糖蛋白（P-gp）的表达进行细胞药物外排，P-糖蛋白是一种具有多种底物的膜转运蛋白。蒽环类药物尤其容易通过P-gp机制诱导耐药性。为了规避外排机制，P-gp介导的耐药性常常通过使用P-gp抑制剂、合成新型类似物或使药物与大分子载体偶联来应对。在本报告中，研究了游离的和弹性蛋白样多肽（ELP）结合的阿霉素（Dox）对敏感的（MES-SA和MCF-7）和多药耐药的（MES-SA/Dx5和NCI/ADR-RES）人癌细胞活力的体外影响。耐药的MES-SA/Dx5细胞对游离Dox的耐药性比敏感的MES-SA细胞高约70倍，而NCI/ADR-RES细胞的耐药性比MCF-7细胞高约30倍。然而，ELP结合的Dox在敏感和耐药细胞系中具有同等的细胞毒性。与被P-gp转运蛋白迅速泵出的游离Dox相反，ELP结合的Dox在MES-SA/Dx5细胞中积累。由于ELP是一种热响应载体，因此研究了热疗对ELP-Dox偶联物细胞毒性的影响。在耐药细胞中，热疗增强了细胞毒性和细胞凋亡。结果表明，ELP-Dox偶联物可能提供一种热靶向实体瘤并克服癌细胞耐药性的方法。
