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

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