ATP?Binding Cassette Transporters Mediated Chemoresistance in MCF-7 Cells: Modulation by PhTAD-Substituted Dihydropyrrole Compounds

Abstract

Purpose: ABC proteins transport many substrates such as antibiotics and drugs. Increase of ABCs lead chemoresistance in can-cer.In view of this information, in our study, we planned to investigate both PhTAD-substituted dihydropyrrole compound's impact on gene expressions of ABC Transporters in the MCF7 cells, and predictive molecular binding sites target on human ABCB1 structure for these compounds.Materials and Methods: The mRNA expression levels of ABCB1, ABCC3, ABCC10, ABCC11, and ABCG2 in the MCF-7 cell were measured by qPCR. Molecular docking assays were realized with both the AutoDock Tools 4.2 and PyMOL 2.4. Also, the interaction analysis was performed by ProteinsPlus web service.Results: Our results revealed that CI, CII, CIII, CV, CVIII, and CXII increased ABCB1 while compound CIV, CVI, CVII, CX, CIX, CXI, CXIII, and CXIV decreased ABCB1. Besides, CI, CIV, CVI, and CVIII upregulate ABCC3, although CVII, CX, CXII, CXIII, and CXIV downregulate ABCC3. Moreover, ABCC10 expression is induced by all compounds. Conversely, ABCC11 expression is reduced by all compounds. Furthermore, CII, CV, and CVI increased ABCG2, while CI, CVII, CVIII, CIX, CX, CXI, CXII, CXIII, and CXIV decreased ABCG2. Also, ABCB1, ABCC3, ABCC11, and ABCG2 parallelly reduced by CVII, CIX, CX, CXI, CXIII, and CXIV. Also, the molecular docking calculation results of CXI and CXIV with high binding energy have shown that tightly modulated ABCB1. Especially, these compounds interact with many hydrogen bonding and hydrophobic site on ABCB1.Conclusion: Our findings indicate that the PhTAD-substituted dihydropyrol containing molecules affect ABC transporters as a potential regulator of cancer chemoresistance.