Synthesis and Characterization of Telmisartan‐Derived Cell Death Modulators to Circumvent Imatinib Resistance in Chronic Myeloid Leukemia

Abstract

New strategies to eradicate cancer stem cells in chronic myeloid leukemia (CML) include a combination of imatinib with peroxisome proliferator‐activated receptor gamma (PPARγ) ligands. Recently, we identified the partial PPARγ agonist telmisartan as effective sensitizer of resistant K562 CML cells to imatinib treatment. Here, the importance of the heterocyclic core on the cell death‐modulating effects of the telmisartan‐derived lead 4′‐((2‐propyl‐1H‐benzo[d]imidazol‐1‐yl)methyl)‐[1,1′‐biphenyl]‐2‐carboxylic acid (3 b) was investigated. Inspired by the pharmacodynamics of HYL‐6d and the selective PPARγ ligand VSP‐51, the benzimidazole was replaced by a carbazole or an indole core. The results indicate no correlation between PPARγ activation and sensitization of resistant CML cells to imatinib. The 2‐COOH derivatives of the carbazoles or indoles achieved low activity at PPARγ, while the benzimidazoles showed 60‐100 % activation. Among the 2‐CO2CH3 derivatives, only the ester of the lead (2 b) slightly activated PPARγ. Sensitizing effects were further observed for this non‐cytotoxic 2 b (80 % cell death), and to a lesser extent for the lead 3 b or the 5‐Br‐substituted ester of the benzimidazoles (5 b).

Cardiovascular Events throughout the Disease Course in Chronic Myeloid Leukaemia Patients Treated with Tyrosine Kinase Inhibitors—A Single-Centre Retrospective Study

“…A new therapeutic option could involve a combination of imatinib and chemical compounds capable of exerting antiproliferative effects against K562-resistant leukaemia cells via PPARγ activation. In this direction, sartans, especially telmisartan, have been extensively studied in recent years [ 44 , 45 , 46 ]. This is an intriguing hypothesis that can also have a potential benefit on the comorbidity treatment (HTN, HF) of CML patients as it is known that the therapeutic plasmatic concentration of telmisartan can be assessed during administration [ 47 ].…”

Reaction Behavior of [1,3-Diethyl-4,5-diphenyl-1H-imidazol-2-ylidene] Containing Gold(I/III) Complexes against Ingredients of the Cell Culture Medium and the Meaning on the Potential Use for Cancer Eradication Therapy

“…The CML cell line K562-R cells was originally described by Hui et al as a Doxorubicin-resistant subclone of the K562 cell line (originally termed as KD225) . K562-R cells are also resistant toward Imatinib, as we described in previous publications. − …”

“… 50 K562-R cells are also resistant toward Imatinib, as we described in previous publications. 51 − 54 …”

Chronic myeloid leukemia-from the Philadelphia chromosome to specific target drugs: A literature review

“…Faced with the possibility of therapy-resistant cells to conventional drugs[ 185 ] or other treatment problems, whether by non-remission or progression of the disease and possible adverse effects, new research is looking for alternatives that treat the CML more effectively and improve the life quality of the patients[ 186 ]. The following topics gather some of the most relevant therapeutic strategies in this context.…”

“…Moreover, it was reported that pioglitazone combined with imatinib increases the apoptotic capacity of tumor cells by a positive regulation of caspase 3, which may mean that a combined therapy with these two drugs can be an alternative for resistant CML treatment[ 186 ]. Telmisartan, a partial agonist of the PPAR-γ, has shown to be effective in circumventing the resistance to imatinib, possibly being more effective than pioglitazone[ 185 ].…”