2. Academic Validation
  3. Overcoming imatinib resistance in chronic myelogenous leukemia cells using non-cytotoxic cell death modulators

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

  • Eur J Med Chem. 2020 Jan 1;185:111748. doi: 10.1016/j.ejmech.2019.111748.
Anna M Schoepf 1,  Stefan Salcher 2,  Petra Obexer 3,  Ronald Gust 4
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Institute of Pharmacy, CMBI - Center for Molecular Biosciences Innsbruck, University of Innsbruck, CCB - Centrum for Chemistry and Biomedicine, Innrain 80-82, 6020, Innsbruck, Austria.
  • 2 Tyrolean Cancer Research Institute, Innrain 66, 6020, Innsbruck, Austria.
  • 3 Tyrolean Cancer Research Institute, Innrain 66, 6020, Innsbruck, Austria; Department of Pediatrics II, Medical University of Innsbruck, Innrain 66, 6020, Innsbruck, Austria.
  • 4 Department of Pharmaceutical Chemistry, Institute of Pharmacy, CMBI - Center for Molecular Biosciences Innsbruck, University of Innsbruck, CCB - Centrum for Chemistry and Biomedicine, Innrain 80-82, 6020, Innsbruck, Austria. Electronic address: ronald.gust@uibk.ac.at.
PMID: 31648125 DOI: 10.1016/j.ejmech.2019.111748
Abstract

Recent studies examined the possibility to overcome imatinib resistance in chronic myeloid leukemia (CML) patients by combination therapy with Peroxisome Proliferator-activated Receptor gamma (PPARγ) ligands. Pioglitazone, a full PPARγ 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 PPARγ agonists on the ability to circumvent resistance, the partial PPARγ 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 PPARγ to more than 40% at 10 μM, 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.

Keywords

Cell death modulators; Chronic myeloid leukemia; Imatinib resistance; Peroxisome proliferator-activated receptor γ; Structure-activity relationship.

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