T-type calcium channel blockers as neuroprotective agents

Kopecky, Benjamin; Liang, Ruqiang; Bao, Jianxin

doi:10.1007/s00424-014-1454-x

Cited by 64 publications

(48 citation statements)

References 81 publications

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“…Of the four selected compounds, manidipine, lacidipine, and benidipine target L-type calcium channels and are clinically used as antihypertensive agents [34], whereas lomerizine targets both Land T-type calcium channels and is generally used in the clinical treatment of migraines [35], as well as the experimental treatment of glaucoma and optic nerve injury [36].…”

Section: Ccbs Inhibit Sphere Formation and Induce Cell Death In Ovarimentioning

confidence: 99%

Calcium Channels as Novel Therapeutic Targets for Ovarian Cancer Stem Cells

Lee

Kim

et al. 2020

IJMS

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Drug resistance in epithelial ovarian cancer (EOC) is reportedly attributed to the existence of cancer stem cells (CSC), because in most cancers, CSCs still remain after chemotherapy. To overcome this limitation, novel therapeutic strategies are required to prevent cancer recurrence and chemotherapy-resistant cancers by targeting cancer stem cells (CSCs). We screened an FDA-approved compound library and found four voltage-gated calcium channel blockers (manidipine, lacidipine, benidipine, and lomerizine) that target ovarian CSCs. Four calcium channel blockers (CCBs) decreased sphere formation, viability, and proliferation, and induced apoptosis in ovarian CSCs. CCBs destroyed stemness and inhibited the AKT and ERK signaling pathway in ovarian CSCs. Among calcium channel subunit genes, three L- and T-type calcium channel genes were overexpressed in ovarian CSCs, and downregulation of calcium channel genes reduced the stem-cell-like properties of ovarian CSCs. Expressions of these three genes are negatively correlated with the survival rate of patient groups. In combination therapy with cisplatin, synergistic effect was shown in inhibiting the viability and proliferation of ovarian CSCs. Moreover, combinatorial usage of manidipine and paclitaxel showed enhanced effect in ovarian CSCs xenograft mouse models. Our results suggested that four CCBs may be potential therapeutic drugs for preventing ovarian cancer recurrence.

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Section: Ccbs Inhibit Sphere Formation and Induce Cell Death In Ovarimentioning

confidence: 99%

Calcium Channels as Novel Therapeutic Targets for Ovarian Cancer Stem Cells

Lee

Kim

et al. 2020

IJMS

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“…This provides a potential therapeutic target, by using drugs that modulate the amount of free Ca 2+ in the cell. Ca 2+ channel blockers, such as those from the dihydropyridine family, may be used to lessen the increase in intracellular Ca 2+ seen in aged neurons [ 82 ]. A step towards replicating the complex architecture of the CNS and assessing Ca 2+ blockade was performed by Chan et al [ 83 ] who used brain slices prepared from a MPTP mouse model for PD.…”

Section: Increased Intracellular Ca 2+ Induces mentioning

confidence: 99%

Interactions between Calcium and Alpha-Synuclein in Neurodegeneration

2014

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In Parkinson’s disease and some atypical Parkinson’s syndromes, aggregation of the α-synuclein protein (α-syn) has been linked to neurodegeneration. Many triggers for pathological α-syn aggregation have been identified, including port-translational modifications, oxidative stress and raised metal ions, such as Ca2+. Recently, it has been found using cell culture models that transient increases of intracellular Ca2+ induce cytoplasmic α-syn aggregates. Ca2+-dependent α-syn aggregation could be blocked by the Ca2+ buffering agent, BAPTA-AM, or by the Ca2+ channel blocker, Trimethadione. Furthermore, a greater proportion of cells positive for aggregates occurred when both raised Ca2+ and oxidative stress were combined, indicating that Ca2+ and oxidative stress cooperatively promote α-syn aggregation. Current on-going work using a unilateral mouse lesion model of Parkinson’s disease shows a greater proportion of calbindin-positive neurons survive the lesion, with intracellular α-syn aggregates almost exclusively occurring in calbindin-negative neurons. These and other recent findings are reviewed in the context of neurodegenerative pathologies and suggest an association between raised Ca2+, α-syn aggregation and neurotoxicity.

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“…The present study demonstrated that an herbal medicine called quercetin, at 50 μM concentration, protected SH-SY5Y cells from bupivacaine-induced cellular death, and was as effective as mibefradil, one T-type calcium channel blocker, at 10 μM concentration. The neuro-protective effects of T-type calcium channel blockers (such as mibefradil) have been reported before [10]. For example, Bancila et al found that mibefradil administration prevented neuronal death after ischemia in a global ischemia rat model [11].…”

Section: Discussionmentioning

confidence: 94%