The role of a Schiff base scaffold, N-(2-hydroxy acetophenone) glycinate-in overcoming multidrug resistance in cancer

Abstract

Drug resistance is a problem that hinders the numerous successes of chemotherapeutic intervention of cancer and continues to be a major obstacle for cures. Till date, several attempts have been made to develop suitable multidrug resistance (MDR) reversing agents. But, throughout the clinical development of MDR reversing agents, patients repeatedly suffer from toxicities. So far, some anticancer activity of Schiff bases which are the condensation products of carbonyl compounds and primary amines and their metal complexes has been described. But, overcoming multidrug resistance, by the use of such small molecules still remain unexplored. Under this backdrop, in search of less toxic and more effective MDR reversing agents our laboratory has developed the different metal chelates of Schiff base N-(2-hydroxy acetophenone)glycinate (NG) which is structurally similar to azatyrosine [L-β-(5-hydroxy-2-pyridyl)-alanine] that inhibits tumor formation by deactivating the c-Raf-1 kinase and c-Ha-ras signalling pathway. A decade-long research proposes possible strategies to overcome MDR by exploiting the chemical nature of such metal chelates. In this review we have catalogued the success of metal chelates of NG to overcome MDR in cancer. The review depict that the problem of MDR can be circumvent by synchronized activation of immunogenic cell death pathways that utilize the components of a host's immune system to kill cancer cells in combination with other conventional strategies. The current wealth of preclinical information promises better understanding of the cellular processes underlying MDR reversing activity of metal derivatives of NG and thus exposes several cellular targets for rational designing of new generation of Schiff base metal chelates as MDR reversing agents.

Keywords: ABC transporter; Apoptosis; Copper N-(2-hydroxyacetophenone)glycinate; CuNG; Doxorubicin resistant Ehrlich ascites carcinoma cells; EAC/Dox; FeNG; Forkhead box P3; FoxP3; GSH; Glutathione; Iron N-(2-hydroxy acetophenone)glycinate; MAP kinase signalling; MAPK; MDR; MDSC; MRP1; Mitogen-activated protein kinase; Multidrug Resistance-associated Protein 1; Multidrug resistance; Myeloid derived suppressor cell; N-(2-hydroxy acetophenone)glycinate; NG; ROS; Reactive oxygen species; Schiff base metal chelates; T regulatory cell (CD4(+)CD25(+)FoxP3(+)); T(Reg); TAM; Tumor-associated macrophage; Zn N-(2-hydroxyacetophenone)glycinate.; ZnNG; reactive oxygen species.