Novel pyrimidine-artesunate hybrids overcome multidrug-resistance in non-small cell lung carcinoma through collateral sensitivity

A series of hybrid compounds based on artesunic acid and pyrimidine were synthesized and tested for their Anticancer activity against non-small cell lung carcinoma (NSCLC), specifically targeting multidrug resistance mediated by P-glycoprotein (P-gp). Preliminary screening showed that artesunate and the hybrid compounds exhibited enhanced cytotoxicity towards resistant NCI-H460/R cells at 5 μM, indicating collateral sensitivity. Dose-response analysis identified compounds 15h and 17a with the most substantial effect, displaying collateral sensitivity indexes (CSI) 4 and 5, respectively, while 15d, 15f, and 15i showed remarkable selectivity for Cancer cells with selectivity indexes (SI) above 10. Mechanistic studies revealed that some hybrids effectively inhibited P-gp activity, outperforming the benchmark inhibitor tariquidar (TQ). Co-treatment of 15h and 17a with P-gp inhibitors indicated that the type of P-gp inhibition matters. Substrate inhibitor dexverapamil (Dex-Ver) lowered cytotoxicity of 15h and 17a, while non-substrate inhibitor TQ, increased it. Computational docking study showed that 17a binds the verapamil-binding pocket of P-gp with greater affinity than dexverapamil (Dex-Ver). The P-gp mechanism and the difference in redox balance between sensitive and resistant NSCLC cells drive collateral sensitivity achieved by 15h and 17a. Overall, the study demonstrates that pyrimidine-artesunate hybrids selectively target MDR Cancer cells, highlighting their potential to overcome drug resistance in Cancer treatment.