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Abstract
Mibefradil is a tetralol derivative originally developed as an antagonist of T-type voltage-gated calcium (Ca2+) channels to treat hypertension when used at nanomolar dosage. More recently, its therapeutic application in hypertension has declined and has been instead repurposed as a treatment of cancer cell proliferation and solid tumor growth. Beyond its function as a Cav blocker, the micromolar concentration of mibefradil can stimulate a rise in [Ca2+]cyt although the mechanism is poorly known. The chanzyme TRPM7 (transient receptor potential melastanin 7), the release of intracellular Ca2+ pools, and Ca2+ influx by ORAI channels have been associated with the increase in [Ca2+]cyt triggered by mibefradil. This study aims to investigate the cellular targets and pathways associated with mibefradil’s effect on [Ca2+]cyt. To address these questions, we monitored changes in [Ca2+]cyt in the specialized mouse epithelial cells (LS8 and ALC) and the widely used HEK-293 cells by stimulating these cells with mibefradil (0.1 μM to 100 μM). We show that mibefradil elicits an increase in [Ca2+]cyt at concentrations above 10 μM (IC50 around 50 μM) and a fast Ca2+ increase capacity at 100 μM. We found that inhibiting IP3 receptors, depleting the ER-Ca2+ stores, or blocking phospholipase C (PLC), significantly decreased the capacity of mibefradil to elevate [Ca2+]cyt. Moreover, the transient application of 100 μM mibefradil triggered Ca2+ influx by store-operated Ca2+ entry (SOCE) mediated by the ORAI channels. Our findings reveal that IP3R and PLC are potential new targets of mibefradil offering novel insights into the effects of this drug.
Highlights
Mibefradil, known as Ro 40–5967, is an organic compound derivative of tetralol that has been used as a Ca2+ channel antagonist (CCA)
Relevant is the use of Ca2+ channel antagonists (CCA), which dilate the arteries and lower blood pressure, being effective in the treatment of angina or cardiac dysrhythmias [34]
Mibefradil was launched as a new potent Ca2+ antagonist in 1997 to inhibit T-type (Cav 3.1–3.3) channels and was used in the treatment of hypertension and angina [4]
Summary
Mibefradil, known as Ro 40–5967, is an organic compound derivative of tetralol that has been used as a Ca2+ channel antagonist (CCA). Patch-clamp studies revealed that mibefradil has an IC50 around 0.3–2.7 μM for Ca2+, Na+, and K+ voltage-dependent currents in HEK-293 cells [1,2,3]. Mibefradil, a T-type voltage-gated calcium (Ca2+) channels (Cav 3.1–3.3) inhibitor, was launched by Roche as Posicor® for the treatment of hypertension and stable angina at doses containing 50– 100 mg once a day [1, 4]. Mibefradil has been used to treat ovarian and pancreatic cancer, glioblastoma and has an anti-proliferative effect on several cancer cell lines [8,9,10,11,12,13]. The anti-proliferative and anti-tumoral properties of mibefradil were dependent on caspase activation, the transfer of Ca2+
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