Abstract
Cancer is a strong global burden with increasing numbers of diseases and ongoing anticancer drug resistance. The number of structurally novel anticancer drugs is strongly limited. They cause high costs for the social health systems. Most critical so-called multidrug resistances (MDR) are caused by transmembrane efflux pumps that transport drugs with various structures out of the cancer cells. Multidrug resistance proteins (MRPs) type 1 and 2 are found overexpressed in various kinds of cancer. There is a strong need for inhibitors of those efflux pumps. We developed novel nonsymmetrical 1,4-dihydropyridines as novel inhibitors of cancer relevant MRP types 1 and 2. The structure-dependent activities of the differently substituted derivatives were evaluated in cellular assays of respective cancer cells and are discussed. Promising candidates were identified. One candidate was demonstrated to resensitize a cisplatin resistant cancer cell line and thus to overcome the anticancer drug resistance.
Highlights
Beside cardiovascular diseases cancer is the most threatening global disease that causes millions of deaths per year [1,2,3]
multidrug resistance (MDR) is mediated by transmembrane efflux pumps
We developed novel 1,4-dihydropyridines as non-symmetrical compounds that have been investigated to inhibit MRP1 and MRP2, both with a non-symmetric framework
Summary
Beside cardiovascular diseases cancer is the most threatening global disease that causes millions of deaths per year [1,2,3]. The resistance mostly includes several anticancer drugs with variable structures as MDR [8] In case of such an induced resistance the only possibility to overcome the resistance is the inhibition of the efflux pumps’ activity in order to increase the intracellular anticancer drug concentration and resensitize the cancer cells towards therapy [9]. We developed novel 1,4-dihydropyridines as innovative inhibitors of the multidrug resistance protein (MRP) type transporters, namely MRP1 and 2 which play the most prominent role in anticancer drug resistance within the MRP family [8]. We developed novel non-symmetrical 1,4-dihydropyridines to investigate them as inhibitors of the non-symmetrical MRP types 1 and 2 They have been evaluated in cancer-derived cellular test systems by the use of a fluorescent substrate that was measured to prove the inhibition effect by an increase of that substrate in the cells. This drug candidate was able to reverse efflux pump driven anticancer drug resistance by restoring the respective drug sensitivity
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