Targeting sensitive and multidrug resistant leukemia cells with a novel benzofuran-isatin conjugate

Area of Science:

• Medicinal Chemistry
• Cancer Biology
• Pharmacology

Background:

• Benzofuran-isatin conjugates show promise in cancer therapy.
• Their efficacy against multidrug-resistant (MDR) tumors remains unexplored.
• Understanding resistance mechanisms is crucial for developing new cancer treatments.

Purpose of the Study:

• To investigate the activity of a novel benzofuran-isatin conjugate, G-5e, against multidrug-resistant cancer cell lines.
• To elucidate the mechanisms underlying G-5e's activity, including collateral sensitivity.
• To evaluate G-5e's potential in overcoming common drug resistance pathways.

Main Methods:

• Screening G-5e in cell lines with known drug resistance mechanisms (P-gp, BCRP, TP53, EGFR).
• Assessing collateral sensitivity in P-glycoprotein overexpressing CEM/ADR5000 cells.
• Analyzing cell cycle progression, autophagy markers (RND2, LC3B), and transcriptomic profiles (NF-κB, ERK1/2 pathways).

Main Results:

• CEM/ADR5000 cells exhibited significant hypersensitivity (collateral sensitivity) to G-5e.
• G-5e induced autophagic cell death via RND2 downregulation and LC3B upregulation.
• Cell cycle arrest at the G0/G1 phase was observed.
• Transcriptomic analysis revealed downregulation of NF-κB and ERK1/2 pathways.

Conclusions:

• Benzofuran-isatin conjugates, like G-5e, demonstrate potential in combating multidrug-resistant cancers.
• RND2 plays a significant role in mediating collateral sensitivity to G-5e.
• G-5e's ability to modulate autophagy and key signaling pathways offers a promising strategy against drug-resistant tumors.