New mechanistic insight on the PIM-1 kinase inhibitor AZD1208 using multidrug resistant human erythroleukemia cell lines and molecular docking simulations.

New mechanistic insight on the PIM-1 kinase inhibitor AZD1208 using multidrug resistant human erythroleukemia cell lines and molecular docking simulations. Curr Top Med Chem. 2019 May 09;: Authors: Marques MB, González-Durruthy M, da Silva Nornberg BF, Oliveira BR, Almeida DV, de Souza Votto AP, Marins LF Abstract PIM-1 is a kinase which has been related to the oncogenic processes like cell survival, proliferation and multidrug resistance (MDR). This kinase is known for its ability to phosphorylate the main extrusion pump (ABCB1) related to the MDR phenotype. In the present work, we testes a new mechanistic insight on the AZD1208 (PIM-1 specific inhibitor) under interaction with chemotherapy agents such as Daunorubicin (DNR) and Vincristine (VCR). In order to verify a potential cytotoxic effect based on pharmacological synergism, two MDR cell lines were used: Lucena resistant to VCR) and FEPS (resistant to DNR), both derived from the K562 non-MDR cell line. Our in vitro results have shown that AZD1208 alone decreases cell viability of MDR cells. However, co-exposure of AZD1208 and DNR or VCR reverses this effect. When we analyzed the ABCB1 activity AZD1208 alone was not able to affect the pump extrusion. Differently, co-exposure of AZD1208 and DNR or VCR impaired ABCB1 activity, which could be explained by compensatory expression of abcb1 or other extrusion pumps not analyzed here. Furthermore, we performed a molecular docking simul...
Source: Current Topics in Medicinal Chemistry - Category: Chemistry Authors: Tags: Curr Top Med Chem Source Type: research