Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA.
Curr Pharm Des. 2011;17(26):2793-802. doi: 10.2174/138161211797440186.
Brain cancer is a devastating disease. Despite extensive research, treatment of brain tumors has been largely ineffective and the diagnosis of brain cancer remains uniformly fatal. Failure of brain cancer treatment may be in part due to limitations in drug delivery, influenced by the ABC drug efflux transporters P-gp and BCRP at the blood-brain and blood-tumor barriers, in brain tumor cells, as well as in brain tumor stem-like cells. P-gp and BCRP limit various anti-cancer drugs from entering the brain and tumor tissues, thus rendering chemotherapy ineffective. To overcome this obstacle, two strategies - targeting transporter regulation and direct transporter inhibition - have been proposed. In this review, we focus on these strategies. We first introduce the latest findings on signaling pathways that could potentially be targeted to down-regulate P-gp and BCRP expression and/or transport activity. We then highlight in detail the new paradigm of P-gp and BCRP working as a "cooperative team of gatekeepers" at the blood-brain barrier, discuss its ramifications for brain cancer therapy, and summarize the latest findings on dual P-gp/BCRP inhibitors. Finally, we provide a brief summary with conclusions and outline the perspectives for future research endeavors in this field.
脑癌是一种毁灭性的疾病。尽管进行了广泛的研究，但脑肿瘤的治疗基本上仍然没有效果，脑癌的诊断仍然是致命的。脑癌治疗的失败可能部分归因于药物输送的限制，这受到血脑和血肿瘤屏障、脑肿瘤细胞以及脑肿瘤干细胞样细胞中的 ABC 药物外排转运蛋白 P-糖蛋白和乳腺癌耐药蛋白的影响。P-糖蛋白和乳腺癌耐药蛋白限制了各种抗癌药物进入大脑和肿瘤组织，从而使化疗无效。为了克服这一障碍，提出了两种策略 - 靶向转运体调节和直接转运体抑制。在这篇综述中，我们重点介绍了这些策略。我们首先介绍了可能被靶向以下调 P-糖蛋白和乳腺癌耐药蛋白表达和/或转运活性的最新信号通路发现。然后，我们详细介绍了 P-糖蛋白和乳腺癌耐药蛋白作为血脑屏障“守门员合作团队”的新范例，讨论了其对脑癌治疗的影响，并总结了双重 P-糖蛋白/乳腺癌耐药蛋白抑制剂的最新发现。最后，我们提供了一个简短的总结，包括结论和对该领域未来研究工作的展望。
