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Tackling resistance in chronic myeloid leukemia: Novel cell death modulators with improved efficacy
Anna M Schoepf1, Stefan Salcher2, Petra Obexer3
1Department 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; Division of Cancer Therapeutics, The Institute of Cancer Research, London, SM2 5NG, United Kingdom.
Abstract:
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.
Insights
New drug compounds overcome imatinib resistance in chronic myeloid leukemia (CML) by targeting the STAT5 pathway. These non-cytotoxic agents restore imatinib efficacy, offering hope for difficult-to-treat CML patients.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Cancer therapy faces challenges due to drug resistance, particularly in chronic myeloid leukemia (CML).
- Imatinib revolutionized CML treatment but cure remains elusive due to resistant cancer stem cells and other factors.
- The STAT5 signaling pathway is implicated in CML cell resistance and presents a therapeutic target.
Purpose of the Study:
- To design and synthesize novel chemosensitizers to overcome imatinib resistance in CML.
- To evaluate the efficacy of these compounds in combination with imatinib against resistant CML cells.
- To elucidate the mechanism of action of the developed chemosensitizers.
Main Methods:
- Synthesis of novel compounds derived from telmisartan, specifically 2-carbonitriles and 2-carboxymethyl esters.
- Assessment of chemosensitizing potency in imatinib-resistant K562 CML cells.
- Evaluation of cytotoxicity, PPARγ agonism, and STAT5 signaling pathway modulation.
Main Results:
- Developed 2-carbonitrile and 2-carboxymethyl ester compounds demonstrated enhanced potency in sensitizing resistant CML cells to imatinib.
- Compound 2d at 5 μM fully overcame imatinib resistance, leading to >76% cell death.
- The most active derivatives suppressed STAT5 phosphorylation, reduced proliferation, and induced cell death in resistant CML cells without inherent cytotoxicity.
Conclusions:
- Novel telmisartan derivatives, particularly carbonitriles, are effective chemosensitizers against imatinib-resistant CML.
- Inhibition of STAT5 phosphorylation is a key mechanism underlying the efficacy of these compounds.
- These findings offer a promising strategy to improve therapeutic outcomes for CML patients with resistant disease.
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