Tackling resistance in chronic myeloid leukemia: Novel cell death modulators with improved efficacy

Eur J Med Chem. 2021 Apr 15:216:113285. doi: 10.1016/j.ejmech.2021.113285. Epub 2021 Feb 18.


The development of resistance poses a serious problem in the therapy of cancer due to the necessity of a multiple-drug and unlimited treatment of affected patients. In chronic myeloid leukemia (CML), the introduction of imatinib has revolutionized the therapy. The persistence of an untreatable cancer stem cell pool and other resistance-causing factors, however, also impede the cure of this malignancy. New therapeutic approaches are therefore essential to overcome current treatment drawbacks. In this regard, an intervention in the STAT5 signaling pathway can significantly improve drug response, as this central signaling node induces the formation of highly resistant CML cells. In the present study, we continued the design of efficient chemosensitizers derived from the partial PPARγ agonist telmisartan. The developed 2-carbonitriles or 2-carboxymethyl esters showed improved potency in sensitizing K562-resistant cells to imatinib treatment, even at concentrations, which are considered patient-relevant. At 5 μM, for instance, 2d sensitized the cells in such a manner that the resistance was fully overcome and the recovered efficacy of imatinib resulted in >76% cell death. Importantly, all compounds were non-cytotoxic per se. A transactivation experiment showed that only the carbonitriles are partial agonists of PPARγ, which does not seem to be involved in the mode of action. Yet, immunoassays revealed a suppression of the STAT5 phosphorylation status by co-application of the most active derivatives with imatinib. This mechanism consequently resulted in reduced cell proliferation and induction of cell death in resistant CML cells.

Keywords: Cell death modulators; Chemosensitizers; Chronic myeloid leukemia; Imatinib resistance; Peroxisome proliferator-activated receptor γ; Signal transducer and activator of transcription 5.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects*
  • COS Cells
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • Drug Design
  • Drug Resistance, Neoplasm / drug effects*
  • Gene Expression Regulation
  • Humans
  • Imatinib Mesylate / therapeutic use
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
  • Nitriles / chemistry*
  • Nitriles / pharmacology
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Phosphorylation / drug effects
  • STAT5 Transcription Factor / antagonists & inhibitors
  • STAT5 Transcription Factor / genetics
  • STAT5 Transcription Factor / metabolism
  • Telmisartan / chemistry
  • Telmisartan / pharmacology
  • Transcriptional Activation / drug effects
  • Tumor Suppressor Proteins / antagonists & inhibitors
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism


  • Antineoplastic Agents
  • Nitriles
  • PPAR gamma
  • STAT5 Transcription Factor
  • STAT5A protein, human
  • Tumor Suppressor Proteins
  • Imatinib Mesylate
  • Telmisartan