Differential Free Intracellular Calcium Release by Class II Antiarrhythmics in Cancer Cell Lines

Area of Science:

• Pharmacology and Molecular Biology
• Cellular Physiology
• Cancer Research

Background:

• Class II antiarrhythmics, or beta-blockers, are widely used to block beta-adrenoceptors.
• The effects of beta-blockers on intracellular calcium (Ca2+i), a critical second messenger, remain largely unknown.
• Understanding Ca2+i regulation is vital for cell function and disease, including cancer.

Purpose of the Study:

• To investigate the differential effects of common beta-blockers (atenolol, metoprolol, propranolol, sotalol) on Ca2+i release.
• To elucidate the specific mechanisms by which propranolol influences Ca2+i release in cancer cells.
• To explore the potential implications of these differential actions on drug pharmacology.

Main Methods:

• Assessed whole-cell currents and intracellular Ca2+i release in PC3 prostate and MCF7 breast cancer cell lines.
• Utilized pharmacological inhibitors including EGTA, dantrolene, 2-aminoethoxydiphenyl borate, 4-chloro-m-cresol, and thapsigargin.
• Examined the effects of preincubation with sotalol and timolol on propranolol-induced Ca2+i release.

Main Results:

• Propranolol, but not atenolol, metoprolol, or sotalol, significantly activated Ca2+i release with distinct kinetics.
• Propranolol-induced Ca2+i release was dependent on extracellular calcium and involved endoplasmic reticulum channels (ryanodine and IP3 receptors).
• Depletion of ER calcium stores abolished propranolol-induced Ca2+i release, and non-selective beta-blockers reduced propranolol's effect.

Conclusions:

• Different beta-blockers exhibit distinct effects on Ca2+i release and whole-cell currents.
• Propranolol stimulates store-operated Ca2+i release through a mechanism involving calcium-induced calcium release and IP3 pathways.
• These findings highlight the differential pharmacology of beta-blockers concerning Ca2+i regulation, with potential clinical relevance.