Timed sequential therapy of the selective T-type calcium channel blocker mibefradil and temozolomide in patients with recurrent high-grade gliomas Mibefradil (MIB), previously approved for treatment of hypertension, is a selective T-type calcium channel blocker with preclinical activity in high-grade gliomas (HGGs). To exploit its presumed mechanism of impacting cell cycle activity (G1 arrest
CACNA1HM1549V mutant calcium channel causes autonomous aldosterone production in HAC15 cells and is inhibited by Mibefradil. We recently demonstrated that a recurrent gain-of-function mutation in a T-type calcium channel, CACNA1H(M1549V), causes a novel Mendelian disorder featuring early-onset primary aldosteronism and hypertension. This variant was found independently in five families ) caused a 7-fold increase in aldosterone levels. Treatment with angiotensin II or increased extracellular potassium levels further stimulated aldosterone production in both CACNA1H(WT)- and CACNA1H(M1549V)-transfected cells. Similar results were obtained for CYP11B2 expression. Inhibition of CACNA1H channels with the T-type calcium channel blocker Mibefradil completely abrogated the effects of CACNA1H
T-type calcium channel antagonists, mibefradil and NNC-55-0396 inhibit cell proliferation and induce cell apoptosis in leukemia cell lines T-type Ca(2+) channels are often aberrantly expressed in different human cancers and participate in the regulation of cell cycle progression, proliferation and death. RT-PCR, Q-PCR, western blotting and whole-cell patch-clamp recording were employed to assess the expression of T-type Ca(2+) channels in leukemia cell lines. The function of T-type Ca(2+) channels in leukemia cell growth and the possible mechanism of the effect of T-type Ca(2+) channel antagonists on cell proliferation and apoptosis were examined in T-lymphoma cell lines. We show that leukemia cell lines exhibited reduced cell growth when treated with T-type Ca(2+) channel inhibitors, mibefradil
Chronic intrathecal infusion of mibefradil, ethosuximide and nickel attenuates nerve ligation-induced pain in rats. T-type Ca(2+) channels (TCC) are important for pain transmission, especially the Ca(V)3.2 subtype. In this study, we examined the effects of intrathecal TCC blockers in the L5/6 spinal nerve ligation pain rat model. Under isoflurane anaesthesia, rats received right L5/6 spinal nerve ligation and intrathecal catheters (attached to an infusion pump) were sited. After surgery, saline, mibefradil, ethosuximide or NiCl2 were given intrathecally for seven days. The right hindpaw withdrawal thresholds to von Frey hair stimuli and withdrawal latencies to radiant heat were measured before and once daily for seven days after surgery. Double immunofluorescence and western blotting
Mibefradil reduces blood glucose concentration in db/db mice Numerous recent studies suggest that abnormal intracellular calcium concentration ([Ca2+]i) is a common defect in diabetic animal models and patients. Abnormal calcium handling is an important mechanism in the defective pancreatic β-cell function in type 2 diabetes. T-type Ca2+ channel antagonists lower blood glucose in type 2 diabetes , but the mechanism remains unknown. We examined the effect of the Ca2+ channel antagonist mibefradil on blood glucose in male db/db mice and phenotypically normal heterozygous mice by intraperitoneal injection. Mibefradil (15 mg/kg, i.p., b.i.d.) caused a profound reduction of fasting blood glucose from 430.92±20.46 mg/dl to 285.20±5.74 mg/dl in three days. The hypoglycemic effect of mibefradil was reproduced
(AD)-like mouse model and mediated neuronal excitability. Genetic knockout of Cav3.2 or T-type calcium channel blocker mibefradil treatment reduced spontaneous and mechanically induced scratching behaviors and skin inflammation in an AD-like mouse model. Substance P and vasoactive intestinal polypeptide levels were increased in the trigeminal ganglia (TG) from AD-like mouse model, and genetic
. The downstream signals linked to this channel activity were studied by ERK1/2 phosphorylation assays in serum, PDGF and TGF-β1 stimulated cells. We also examined their proliferative responses in the presence of the TTCC inhibitors mibefradil and TH1177. We demonstrate a complete loss of ERK1/2 phosphorylation in response to multiple stimuli (serum, PDGF, TGF-β1) in Ca3.1 SKO clone, whereas the Ca3.2 SKO clone a role in cell proliferation. Whereas the Ca3.1 isoform is required for stimulated phosphorylation of ERK1/2, the Ca 3.2 isoform is not. Our data also suggest that neither isoform is necessary for cell proliferation and that the anti-proliferative effects of mibefradil and TH1177 are not isoform-specific. These findings are consistent with data from in vivo rat mesangial proliferation Thy1 models
was localized on the surface of the cilia, and that for Cav3.3 was localized in the cilia and at the base of the cilia. The existence of Cav3.1 and Cav3.3 was confirmed at the protein level by Western blot and at the transcriptional level by real-time RT-PCR. Specific blockers of T-type VGCC, mibefradil and NNC 55-0396, significantly inhibited CBF. These blockers also inhibited a CBF increase induced by 8 -bromo-cAMP/8-bromo-cGMP and significantly lowered the intracellular Ca2+ level of isolated ciliated cells in a time-dependent manner. On the other hand, the ATP release from the nasal mucosa was not changed by mibefradil or NNC 55-0396. These results indicate that T-type VGCC α1 subunits, Cav3.1 and Cav3.3, exist at the cilia of the nasal epithelial cells and participate in the regulation of ciliary
Inhibition of glioblastoma and enhancement of survival via the use of mibefradil in conjunction with radiosurgery. The survival of patients with high-grade gliomas remains unfavorable. Mibefradil, a T-type calcium channel inhibitor capable of synchronizing dividing cells at the G1 phase, has demonstrated potential benefit in conjunction with chemotherapeutic agents for gliomas in in vitro studies. In vivo study of mibefradil and radiosurgery is lacking. The authors used an intracranial C6 glioma model in rats to study tumor response to mibefradil and radiosurgery. Two weeks after implantation of C6 cells into the animals, each rat underwent MRI every 2 weeks thereafter for 8 weeks. After tumor was confirmed on MRI, the rats were randomly assigned to one of the experimental groups. Tumor
mibefradil induced cell death, differentiation and susceptibility to MAPKi in vitro and in vivo. In summary, we show that partial reprogramming of melanoma cells induces de-differentiation and adaptation to MAPKi. Moreover, we postulated a calcium channel blocker such as mibefradil, as a potential candidate to restore sensitivity to MAPKi in adaptive melanoma cells.
the expression of inducible nitric oxide synthase through the p38 signaling pathway in cultured SGCs. In turn, L-arginine (nitric oxide donor) was able to enhance orofacial pain by upregulating CGRP expressions in vivo. In cultured trigeminal neurons, L-arginine upregulated the expression of CGRP, and this effect was diminished by cilnidipine (N-type calcium channel blocker) while not by mibefradil (L-type
afferent nerve fibers to neuropathic pain in rats with spared nerve injury (SNI). Aβ-, Aδ- and C-fibers of the uninjured sural nerve were sensitized revealed by single-unit recording, which were accompanied by accumulation of Ca3.2 T-type calcium channel proteins shown by Western blotting. Application of mibefradil, a T-type calcium channel blocker, to sural nerve receptive fields increased mechanical thresholds of Aβ-, Aδ- and C-fibers, confirming the functional involvement of accumulated channels in the sural nerve in SNI rats. Finally, perineural application of mibefradil or TTA-P2 to the uninjured sural nerve alleviated mechanical allodynia in SNI rats. These results suggest that axonal accumulation of Ca3.2 T-type calcium channels plays an important role in the uninjured sural nerve sensitization
of LVA channels at all ages. The Cav 3.1 subunit (α1G) was the most expressed. T-type channel blockers mibefradil and TTA-A significantly inhibited insulin secretion at 5.6 mM glucose, which suggests a physiological role for T-type channels at basal glucose conditions. Both, nifedipine and TTA-A, drastically decreased the beta-cell subpopulation that secretes more insulin, in both basal and stimulating
April 2015 and April 2016, the potential of verapamil (VP), mibefradil (MF), L703,606 (L7), and primaquine (PQ) to reverse CQ resistance was assessed in 46 and 34 clinical isolates in Papua, Indonesia, where CQ resistance is present in both species, using a modified schizont maturation assay. In , CQ 50% inhibitory concentrations (ICs) were reduced when CQ was combined with VP (1.4-fold), MF (1.2
to assess RGC apoptosis following an injection with the T type Ca2+ channel blocker. Ca2+ channels, mainly the T type, were upregulated in COH rat retinas when compared with the sham group (P<0.01). Additionally, the Cav3.2 subunit of T type calcium channels was predominantly expressed in Müller cells and RGCs, such as ephrinB2. Furthermore, an intravitreal injection of the Ca2+ channel blocker Mibefradil
acute nocifensive responses produced by interleukin-1 beta, which was similar to that achieved by elimination of T-type channel activity with the channel blockers, mibefradil, or TTA-A2. Finally, this upregulation could be maintained in dorsal root ganglion neuron cultures exposed overnight to interleukin-1 beta, while the copresence of interleukin-1 receptor antagonist or the dampening of neuronal