New uracil analog as inhibitor/modulator of ABC transporters or/and NF-κB in taxol-resistant MCF-7/Tx cell line.

PURPOSE:The global increase in breast cancer cases necessitates ongoing exploration of advanced therapies. Taxol (Tx), an initial breast cancer treatment, induces mitotic arrest but faces limitations due to side effects and the development of resistance. Addressing Tx resistance involves understanding the complex molecular mechanisms, including alterations in tubulin dynamics, NF-κB signaling, and overexpression of ABC transporters (ABCB1 and ABCG2), leading to multidrug resistance (MDR). METHODS:Real-time PCR and ELISA kits were used to analyze ABCB1, ABCG2 and NF-κB gene and protein expression levels, respectively. An MDR test assessed the resistance cell phenotype. RESULTS:MCF-7/Tx cells exhibited a 24-fold higher resistance to Tx. Real-time PCR and ELISA analysis revealed the upregulation of ABCB1, ABCG2, and NF-κB. U-359 significantly downregulated both ABCB1 and ABCG2 gene and protein levels. Co-incubation with Tx and U-359 further decreased the mRNA and protein expression of these transporters. The MDR test indicated that U-359 increased MDR dye retention, suggesting its potential as an MDR inhibitor. U-359 and Tx, either individually or combined, modulated NF-κBp65 protein levels. CONCLUSION:The development of a Taxol-resistant MCF-7 cell line provided valuable insights. U-359 demonstrated effectiveness in reducing the expression of ABC transporters and NF-κB, suggesting a potential solution for overcoming multidrug resistance in breast cancer cells. The study recommends a strategy to enhance the sensitivity of cancer cells to chemotherapy by integrating U-359 with traditional drugs.