Anti-invasive effects of minoxidil on human breast cancer cells: combination with ranolazine

Abstract

A plethora of ion channels have been shown to be involved systemically in the pathophysiology of cancer and ion channel blockers can produce anti-metastatic effects. However, although ion channels are known to frequently function in concerted action, little is known about possible combined effects of ion channel modulators on metastatic cell behaviour. Here, we investigated functional consequences of pharmacologically modulating ATP-gated potassium (KATP) channel and voltage-gated sodium channel (VGSC) activities individually and in combination. Two triple-negative human breast cancer cell lines were used: MDA-MB-231 and MDA-MB-468, the latter mainly for comparison. Most experiments were carried out on hypoxic cells. Electrophysiological effects were studied by whole-cell patch clamp recording. Minoxidil (a KATP channel opener) and ranolazine (a blocker of the VGSC persistent current) had no effect on cell viability and proliferation, alone or in combination. In contrast, invasion was significantly reduced in a dose-dependent manner by clinical concentrations of minoxidil and ranolazine. Combining the two drugs produced significant additive effects at concentrations as low as 0.625 μM ranolazine and 2.5 μM minoxidil. Electrophysiologically, acute application of minoxidil shifted VGSC steady-state inactivation to more hyperpolarised potentials and slowed recovery from inactivation, consistent with inhibition of VGSC activation. We concluded (i) that clinically relevant doses of minoxidil and ranolazine individually could inhibit cellular invasiveness dose dependently and (ii) that their combination was additionally effective. Accordingly, ranolazine, minoxidil and their combination may be repurposed as novel anti-metastatic agents.