Cepharanthine, a novel selective ANO1 inhibitor with potential for lung adenocarcinoma therapy

Area of Science:

• Ion channel physiology
• Cancer biology
• Pharmacology

Background:

• Anoctamin-1 (ANO1), also known as TMEM16A, is a Ca2+-activated Cl- channel crucial for physiological functions and implicated in tumor growth.
• Identifying specific modulators of ANO1 is vital for understanding its role in disease and developing targeted therapies.

Purpose of the Study:

• To identify natural compounds that inhibit ANO1 channel activity.
• To investigate the potential of cepharanthine as an anticancer agent targeting ANO1.

Main Methods:

• Screening of 530 natural compounds to identify ANO1 blockers.
• In vitro electrophysiology to assess inhibitory effects on ANO1, ANO2, ANO6, and VRAC currents.
• Cell-based assays to evaluate effects on lung adenocarcinoma cell proliferation, migration, and apoptosis.
• In vivo xenograft mouse models to assess tumor growth inhibition.

Main Results:

• Cepharanthine identified as a potent ANO1 blocker (IC50 = 11.2 ± 0.9 μM).
• Specific amino acid residues (Lys384, Arg535, Thr539, Glu624) in ANO1 are critical for cepharanthine's inhibitory action.
• Cepharanthine selectively inhibited ANO1 and ANO2 but showed limited effects on ANO6 and VRAC.
• Cepharanthine suppressed lung cancer cell proliferation and migration, induced apoptosis, and significantly inhibited tumor growth in vivo.

Conclusions:

• Cepharanthine is a specific and potent inhibitor of ANO1 channels.
• Cepharanthine demonstrates significant anticancer effects against lung adenocarcinoma, suggesting a novel therapeutic mechanism.
• These findings highlight cepharanthine's potential for further investigation in cancer therapy and ANO1 channel research.