Overcoming imatinib resistance in chronic myelogenous leukemia cells using non-cytotoxic cell death modulators

Area of Science:

• Oncology
• Pharmacology
• Biochemistry

Background:

• Imatinib resistance is a significant challenge in chronic myeloid leukemia (CML) treatment.
• Peroxisome proliferator-activated receptor gamma (PPARγ) ligands have shown potential in overcoming this resistance.
• Pioglitazone, a full PPARγ agonist, improved patient survival by targeting CML stem cells.

Purpose of the Study:

• To investigate the role of the pharmacological profile of PPARγ agonists in circumventing imatinib resistance.
• To synthesize and evaluate novel 4-substituted benzimidazole derivatives as potential CML therapeutics.
• To assess the efficacy of these derivatives in combination with imatinib against resistant CML cells.

Main Methods:

• Synthesis of novel 4-substituted benzimidazole derivatives bearing a [1,1'-biphenyl]-2-carboxamide moiety.
• Evaluation of PPARγ activation by these compounds.
• Assessment of their ability to sensitize K562-resistant CML cells to imatinib.
• Comparison of cell death modulating properties with pioglitazone.

Main Results:

• Novel benzimidazole derivatives, particularly compounds 18a-f, sensitized imatinib-resistant K562 cells to imatinib.
• These derivatives, activating PPARγ below 40% at 10 μM, restored imatinib's cytotoxicity.
• The novel compounds exhibited superior cell death modulating properties compared to pioglitazone.
• The tested compounds were non-cytotoxic alone but demonstrated antitumor potency in combination with imatinib.

Conclusions:

• Partial PPARγ agonists, specifically novel benzimidazole derivatives, can effectively overcome imatinib resistance in CML.
• These compounds exhibit potent antitumor activity exclusively in combination with imatinib, without inherent cytotoxicity.
• The findings highlight the therapeutic potential of targeted PPARγ modulation in resistant CML.