Propranolol inhibits neonatal Nav1.5 activity and invasiveness of MDA-MB-231 breast cancer cells: Effects of combination with ranolazine

The MDA-MB-231 cell line was used as a model of triple negative breast Cancer to investigate the interaction of β-adrenergic receptor (β-AR) and voltage-gated Sodium Channel (VGSC). There was significant (86%) overlap in their expression. Short-term (acute) application of the β-AR antagonist propranolol (25 μM) led to reduction of peak current and quickening of current inactivation (the latter occurred only in 5% fetal bovine serum). Long-term (48 hr) incubation with propranolol (25 μM) resulted in several changes in VGSC characteristics: shifts in (a) current-voltage relationship and (b) steady-state inactivation, both to more negative potentials and (c) the slowing of recovery from inactivation. We then investigated the effects of propranolol and ranolazine, a blocker of VGSC activity, alone and in combination, on lateral motility and Matrigel invasion. These assays were carried out under hypoxic conditions more representative of tumor progression. Propranolol (2.5 and 25 μM) and ranolazine (5 μM), and their combination inhibited lateral motility. Also, propranolol (25 μM) and ranolazine (5 μM), and their combination inhibited invasion. However, no synergy was observed in the pharmacological combinations for both assays. Propranolol also significantly decreased total neonatal Nav1.5 protein expression, the predominant VGSC subtype expressed in these cells. We conclude (a) that β-AR and VGSC are functionally coupled in MDA-MB-231 cells; (b) that propranolol has direct blocking action on the VGSC; (c) that the action of propranolol is modulated by serum; and (d) that the antimetastatic cellular effects of propranolol and ranolazine are not additive.

breast cancer; metastasis; propranolol; ranolazine; voltage-gated sodium channel; β-adrenergic receptor.