Overcoming imatinib resistance in chronic myelogenous leukemia cells using non-cytotoxic cell death modulators

Recent studies examined the possibility to overcome imatinib resistance in chronic myeloid leukemia (CML) patients by combination therapy with peroxisome proliferator-activated receptor gamma (PPAR gamma) ligands. Pioglitazone, a full PPAR gamma agonist, improved the survival of patients by the gradual elimination of the residual CML stem cell pool. To evaluate the importance of the pharmacological profile of PPAR gamma agonists on the ability to circumvent resistance, the partial PPAR gamma agonist 4'-((2-propyl-1H-benzo[d] imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid, derived from telmisartan, and other related derivatives were investigated. The 4-substituted benzimidazole derivatives bearing a [1,1'-biphenyl]-2-carboxamide moiety sensitized K562-resistant cells to imatinib treatment Especially the derivatives 18a-f, which did not activate PPAR gamma to more than 40% at 10 mu M, retrieved the cytotoxicity of imatinib in these cells. The cell death modulating properties were higher than that of pioglitazone. It is of interest to note that all novel compounds were not cytotoxic neither on non-resistant nor on resistant cells. They exerted antitumor potency only in combination with imatinib. (C) 2019 Elsevier Masson SAS. All rights reserved.