Research Group of Drug Development, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, 06120 Halle, Germany.
Department of Clinical Pharmacy, Institute of Pharmacy, Ernst Moritz Arndt University Greifswald, 17489 Greifswald, Germany.
Int J Mol Sci. 2021 May 12;22(10):5098. doi: 10.3390/ijms22105098.
Within the last decades cancer treatment improved by the availability of more specifically acting drugs that address molecular target structures in cancer cells. However, those target-sensitive drugs suffer from ongoing resistances resulting from mutations and moreover they are affected by the cancer phenomenon of multidrug resistance. A multidrug resistant cancer can hardly be treated with the common drugs, so that there have been long efforts to develop drugs to combat that resistance. Transmembrane efflux pumps are the main cause of the multidrug resistance in cancer. Early inhibitors disappointed in cancer treatment without a proof of expression of a respective efflux pump. Recent studies in efflux pump expressing cancer show convincing effects of those inhibitors. Based on the molecular symmetry of the efflux pump multidrug resistant protein (MRP) 4 we synthesized symmetric inhibitors with varied substitution patterns. They were evaluated in a MRP4-overexpressing cancer cell line model to prove structure-dependent effects on the inhibition of the efflux pump activity in an uptake assay of a fluorescent MRP4 substrate. The most active compound was tested to resentisize the MRP4-overexpressing cell line towards a clinically relevant anticancer drug as proof-of-principle to encourage for further preclinical studies.
在过去的几十年中，癌症治疗得到了改善，因为有了更多针对癌细胞分子靶结构的特效药物。然而，这些靶标敏感药物由于突变而持续产生耐药性，此外，它们还受到癌症多药耐药现象的影响。多药耐药性的癌症很难用常用药物治疗，因此人们长期以来一直致力于开发药物来对抗这种耐药性。跨膜外排泵是癌症多药耐药性的主要原因。早期的抑制剂在癌症治疗中令人失望，因为没有证据表明存在相应的外排泵表达。最近在表达外排泵的癌症中的研究显示出这些抑制剂的令人信服的效果。基于外排泵多药耐药蛋白（MRP）4 的分子对称性，我们合成了具有不同取代模式的对称抑制剂。它们在过表达 MRP4 的癌细胞系模型中进行了评估，以在摄取荧光 MRP4 底物的测定中证明对抑制外排泵活性的结构依赖性影响。最有效的化合物被测试为过表达 MRP4 的细胞系重新敏化，以针对一种临床相关的抗癌药物作为原理证明，以鼓励进一步进行临床前研究。
