Digoxin enhances radiation response in radioresistant A549 cells by reducing protein phosphatase 2A

Area of Science:

• Oncology
• Molecular Biology
• Radiotherapy Research

Background:

• Protein phosphatase 2A (PP2A) is a key enzyme often acting as a tumor suppressor.
• PP2A inhibition can accelerate cell growth but also sensitize damaged cells to radiotherapy.
• Non-small-cell lung cancer (NSCLC) frequently exhibits radioresistance, necessitating novel therapeutic strategies.

Purpose of the Study:

• To investigate the radiosensitizing effects of digoxin, a PP2A inhibitor, in NSCLC cells.
• To evaluate the efficacy of combining digoxin with ionizing radiation (IR) in preclinical models of NSCLC.
• To elucidate the molecular mechanisms underlying digoxin's radiosensitizing properties.

Main Methods:

• Utilized two NSCLC cell lines (H460 and A549) with varying radiation sensitivities.
• Administered digoxin alone and in combination with IR to cell cultures and xenografts.
• Assessed cell proliferation, clonogenic survival, cell cycle progression, DNA damage, and protein expression (PP2A, p53, cyclins, CDKs, p-ATM).

Main Results:

• Digoxin inhibited NSCLC cell proliferation, particularly in radioresistant A549 cells.
• The combination of digoxin and IR significantly reduced clonogenic survival and tumor growth in A549 xenografts.
• Digoxin suppressed PP2A expression, modulated cell cycle regulators, enhanced IR-induced DNA damage, and increased p-ATM foci formation.

Conclusions:

• Digoxin acts as a PP2A inhibitor with significant radiosensitizing effects in radioresistant NSCLC.
• The combination of digoxin and IR demonstrates a synergistic effect, offering a potential therapeutic strategy for radioresistant lung cancer.
• Digoxin's ability to enhance DNA damage and alter cell cycle progression contributes to its radiosensitizing properties.