New Dual P-Glycoprotein (P-gp) and Human Carbonic Anhydrase XII (hCA XII) Inhibitors as Multidrug Resistance (MDR) Reversers in Cancer Cells

Abstract

In a continuing search of dual P-gp and hCA XII inhibitors, we synthesized and studied new N,N-bis(alkanol)amine aryl diester derivatives characterized by the presence of a coumarin group. These hybrids contain both P-gp and hCA XII binding groups to synergistically overcome the P-gp-mediated multidrug resistance (MDR) in cancer cells expressing both P-gp and hCA XII. Indeed, hCA XII modulates the efflux activity of P-gp and the inhibition of hCA XII reduces the intracellular pH, thereby decreasing the ATPase activity of P-gp. All compounds showed inhibitory activities on P-gp and hCA XII proteins taken individually, and many of them displayed a synergistic effect in HT29/DOX and A549/DOX cells that overexpress both P-gp and hCA XII, being more potent than in K562/DOX cells overexpressing only P-gp. Compounds 5 and 14 were identified as promising chemosensitizer agents for selective inhibition in MDR cancer cells overexpressing both P-gp and hCA XII.

4-(3-Phenyl-4-(3,4,5-trimethoxybenzoyl)-1H-pyrrol-1-yl)benzenesulfonamide, a Novel Carbonic Anhydrase and Wnt/β-Catenin Signaling Pathway Dual-Targeting Inhibitor with Potent Activity against Multidrug Resistant Cancer Cells

“…To test the efficacy of compound 15 , we chose the DOX-sensitive colon cancer HT29 cells, a cell line expressing low levels of P-gp, and its resistant counterpart, the cell line HT29/DX, selected stepwise in media with increasing concentrations of DOX resulting in expression of a high level of P-gp . As a cancer model, the HT29 and HT29/DX pair has been extensively used and characterized for DOX resistance and pharmacological efficacy by our group, , and the cell line pair has important translational potential. However, HT29/DX cells also express other ABC transporters including MRP1, MRP2, MRP3, MRP5, and BCRP .…”

Novel fused pyran derivatives induce apoptosis and target cell cycle progression in anticancer efficacy against multiple cell lines

“…Despite the progress in the development of chemotherapeutic agents, several new targetspecific and improved anticancer agents with minimum/no side effects are essential to tackle drug resistance. [46][47][48] According to the U.S. Food and Drug Administration (FDA) database, nearly 60% of small-molecule drugs are nitrogencontaining heterocycles. 49 Incorporation of nitrogen atoms or N-based heterocycles in a pharmacophore such as a fused pyran may not only increase its water solubility but also enhance the binding to a variety of biological targets such as enzymes and receptors.…”

“…Despite the progress in the development of chemotherapeutic agents, several new target-specific and improved anticancer agents with minimum/no side effects are essential to tackle drug resistance. 46–48…”

Discovery of benzochromene derivatives first example with dual cytotoxic activity against the resistant cancer cell MCF-7/ADR and inhibitory effect of the P -glycoprotein expression levels

“…Alongside its anti-proliferative features, chromene derivatives exhibited a DNA binding ability, the inhibition of the Bcl-2 protein 26 and a high potency for the hAChE 36 . One of the main molecular mechanisms shared in failure of chemotherapy is multi-drug resistance (MDR) 37 , 38 . The main cause of MDR is overexpression of the ABC transporters, such as permeability glycoprotein ( P -glycoprotein [ P -gp)), multidrug resistance protein 1 (MDR1), and ATP-binding cassette sub-family B member 1 (ABCB1), (DGAT-1), and (hCA XII) inhibitors 38–40 .…”

“…One of the main molecular mechanisms shared in failure of chemotherapy is multi-drug resistance (MDR) 37 , 38 . The main cause of MDR is overexpression of the ABC transporters, such as permeability glycoprotein ( P -glycoprotein [ P -gp)), multidrug resistance protein 1 (MDR1), and ATP-binding cassette sub-family B member 1 (ABCB1), (DGAT-1), and (hCA XII) inhibitors 38–40 . In addition, P -gp/(ABCB1) plays a main role in the multidrug-resistant phenotype in cancer mediating MDR 41 .…”