Dual Inhibitors of P-gp and Carbonic Anhydrase XII (hCA XII) against Tumor Multidrug Resistance with Piperazine Scaffold

TL;DR

Researchers developed new piperazine-based compounds that can inhibit two proteins involved in cancer drug resistance, potentially improving cancer treatment effectiveness.

Contribution

The study introduces dual inhibitors of P-gp and hCA XII with a synergistic mechanism to overcome multidrug resistance in cancer cells.

Findings

Compound 33 showed the best activity in reversing multidrug resistance by enhancing doxorubicin's cytotoxicity and accumulation in resistant cells.

Compounds 13, 27, and 32 induced collateral sensitivity in multidrug-resistant cancer cells.

The compounds demonstrated good inhibitory activity against both P-gp and hCA XII proteins individually.

Abstract

A new series of piperazine derivatives were synthesized and studied with the aim of obtaining dual inhibitors of P-glycoprotein (P-gp) and carbonic anhydrase XII (hCA XII) to synergistically overcome the P-gp-mediated multidrug resistance (MDR) in cancer cells expressing the two proteins, P-gp and hCA XII. Indeed, these hybrid compounds contain both P-gp and hCA XII binding groups on the two nitrogen atoms of the heterocyclic ring. All compounds showed good inhibitory activity on each protein (P-gp and hCA XII) studied individually, and many of them showed a synergistic effect in the resistant HT29/DOX and A549/DOX cell lines which overexpress both the target proteins. In particular, compound 33 displayed the best activity by enhancing the cytotoxicity and intracellular accumulation of doxorubicin in HT29/DOX and A549/DOX cells, thus resulting as promising P-gp-mediated MDR reverser with a synergistic mechanism. Furthermore, compounds 13, 27 and 32 induced collateral sensitivity (CS) in MDR cells, as they were more cytotoxic in resistant cells than in the sensitive ones; their CS mechanisms were extensively investigated.

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