Feedback

Circumventing Imatinib Resistance in Chronic Myeloid Leukemia: Novel Telmisartan-based Chemosensitizers with Improved Efficacyand Stability

Affiliation
Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Innsbruck, CCB-Centrum for Chemistry and Biomedicine, Innrain 80-82, 6020 Innsbruck, Austria
Gebhart, Maximilian;
Affiliation
Department of Pharmacognosy, Institute of Pharmacy, University of Innsbruck, CCB-Centrum for Chemistry and Biomedicine, Innrain 80-82, 6020 Innsbruck, Austria
Alilou, Mostafa;
Affiliation
Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Innsbruck, CCB-Centrum for Chemistry and Biomedicine, Innrain 80-82, 6020 Innsbruck, Austria
Gust, Ronald;
Affiliation
Department of Internal Medicine V, Hematology and Oncology, CCCI- Comprehensive Cancer Center Innsbruck, Medical University Innsbruck, Innsbruck, Austria
Salcher, Stefan

Chronic myeloid leukemia (CML) is a myeloproliferative disease caused by the mutation and proliferation of a monoclonal multipotent hematopoietic progenitor cell. Following gene products show a dysregulated tyrosine kinase activity resulting in enhanced proliferation and resistance to apoptosis of CML. Nowadays, targeted therapy of CML with tyrosine kinase inhibitors (TKIs) is available. However, the inability to attain a complete molecular response in most patients due to TKI-resistant cancer cells, has necessitated the exploration of new therapeutic methods to effectively combat these resistances. Previous studies performed by our group indicated that TKI-resistant cells can be efficiently targeted by a combination therapy of Imatinib and derivatives of the angiotensin 2 antagonist Telmisartan. In the present investigation, we continued designing chemosensitizers based on Telmisartan with the intention to improve their efficacy and particularly their stability while maintaining their selectivity. To evaluate the activity and selectivity of our developed compounds we performed a modified MTT assay with wild type K562 CML cells and their respective Imatinib resistant subclone K562-R. With the new compounds, we could increase the cytotoxic activity of Imatinib on resistant CML cells from 10% to >90%. In addition, the compounds were per se non-cytotoxic. The stability of the ester derivatives was investigated in the presence of porcine liver esterase using a validated HPLC method. Crucially, the designed ester derivatives demonstrated markedly enhanced stability against esterase cleavage. These advancements are a significant step towards future in vivo studies, as they promise to enhance the bioavailability and the therapeutic efficacy of these compounds.

Cite

Citation style:
Could not load citation form.

Access Statistic

Total:
Downloads:
Abtractviews:
Last 12 Month:
Downloads:
Abtractviews:

Rights

Use and reproduction: