Novel Phenolic Inhibitors of Small/Intermediate-Conductance Ca(2+)-Activated K(+) Channels, KCa3.1 and KCa2.3

Aida Olivan-Viguera, Marta Sofía Valero, María Divina Murillo, Heike Wulff, Angel-Luis García-Otín, José-Miguel Arbonés-Mainar, Ralf Köhler

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

BACKGROUND: KCa3.1 channels are calcium/calmodulin-regulated voltage-independent K(+) channels that produce membrane hyperpolarization and shape Ca(2+)-signaling and thereby physiological functions in epithelia, blood vessels, and white and red blood cells. Up-regulation of KCa3.1 is evident in fibrotic and inflamed tissues and some tumors rendering the channel a potential drug target. In the present study, we searched for novel potent small molecule inhibitors of KCa3.1 by testing a series of 20 selected natural and synthetic (poly)phenols, synthetic benzoic acids, and non-steroidal anti-inflammatory drugs (NSAIDs), with known cytoprotective, anti-inflammatory, and/or cytostatic activities. METHODOLOGYPRINCIPAL FINDINGS: In electrophysiological experiments, we identified the natural phenols, caffeic acid (EC50 1.3 µM) and resveratrol (EC50 10 µM) as KCa3.1 inhibitors with moderate potency. The phenols, vanillic acid, gallic acid, and hydroxytyrosol had weak or no blocking effects. Out of the NSAIDs, flufenamic acid was moderately potent (EC50 1.6 µM), followed by mesalamine (EC50≥10 µM). The synthetic fluoro-trivanillic ester, 13b ([3,5-bis[(3-fluoro-4-hydroxy-benzoyl)oxymethyl]phenyl]methyl 3-fluoro-4-hydroxy-benzoate), was identified as a potent mixed KCa2/3 channel inhibitor with an EC50 of 19 nM for KCa3.1 and 360 pM for KCa2.3, which affected KCa1.1 and Kv channels only at micromolar concentrations. The KCa3.1/KCa2-activator SKA-31 antagonized the 13b-blockade. In proliferation assays, 13b was not cytotoxic and reduced proliferation of 3T3 fibroblasts as well as caffeic acid. In isometric vessel myography, 13b increased contractions of porcine coronary arteries to serotonin and antagonized endothelium-derived hyperpolarization-mediated vasorelaxation to pharmacological KCa3.1/KCa2.3 activation. CONCLUSIONSSIGNIFICANCE: We identified the natural phenols, caffeic acid and resveratrol, the NSAID, flufenamic acid, and the polyphenol 13b as novel KCa3.1 inhibitors. The high potency of 13b with pan-activity on KCa3.1/KCa2 channels makes 13b a new pharmacological tool to manipulate inflammation and cancer growth through KCa3.1/KCa2 blockade and a promising template for new drug design.
OriginalsprogEngelsk
TidsskriftP L o S One
Vol/bind8
Udgave nummer3
Sider (fra-til)e58614
ISSN1932-6203
DOI
StatusUdgivet - 2013

Fingeraftryk

potassium channels
phenols
Phenols
nonsteroidal anti-inflammatory agents
caffeic acid
Flufenamic Acid
Anti-Inflammatory Agents
resveratrol
Pharmaceutical Preparations
Benzoates
Myography
Vanillic Acid
benzoic acids
Mesalamine
vanillic acid
neoplasms
vasodilation
new drugs
acids
benzoates

Citer dette

Olivan-Viguera, A., Valero, M. S., Murillo, M. D., Wulff, H., García-Otín, A-L., Arbonés-Mainar, J-M., & Köhler, R. (2013). Novel Phenolic Inhibitors of Small/Intermediate-Conductance Ca(2+)-Activated K(+) Channels, KCa3.1 and KCa2.3. P L o S One, 8(3), e58614. https://doi.org/10.1371/journal.pone.0058614
Olivan-Viguera, Aida ; Valero, Marta Sofía ; Murillo, María Divina ; Wulff, Heike ; García-Otín, Angel-Luis ; Arbonés-Mainar, José-Miguel ; Köhler, Ralf. / Novel Phenolic Inhibitors of Small/Intermediate-Conductance Ca(2+)-Activated K(+) Channels, KCa3.1 and KCa2.3. I: P L o S One. 2013 ; Bind 8, Nr. 3. s. e58614.
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title = "Novel Phenolic Inhibitors of Small/Intermediate-Conductance Ca(2+)-Activated K(+) Channels, KCa3.1 and KCa2.3",
abstract = "BACKGROUND: KCa3.1 channels are calcium/calmodulin-regulated voltage-independent K(+) channels that produce membrane hyperpolarization and shape Ca(2+)-signaling and thereby physiological functions in epithelia, blood vessels, and white and red blood cells. Up-regulation of KCa3.1 is evident in fibrotic and inflamed tissues and some tumors rendering the channel a potential drug target. In the present study, we searched for novel potent small molecule inhibitors of KCa3.1 by testing a series of 20 selected natural and synthetic (poly)phenols, synthetic benzoic acids, and non-steroidal anti-inflammatory drugs (NSAIDs), with known cytoprotective, anti-inflammatory, and/or cytostatic activities. METHODOLOGYPRINCIPAL FINDINGS: In electrophysiological experiments, we identified the natural phenols, caffeic acid (EC50 1.3 µM) and resveratrol (EC50 10 µM) as KCa3.1 inhibitors with moderate potency. The phenols, vanillic acid, gallic acid, and hydroxytyrosol had weak or no blocking effects. Out of the NSAIDs, flufenamic acid was moderately potent (EC50 1.6 µM), followed by mesalamine (EC50≥10 µM). The synthetic fluoro-trivanillic ester, 13b ([3,5-bis[(3-fluoro-4-hydroxy-benzoyl)oxymethyl]phenyl]methyl 3-fluoro-4-hydroxy-benzoate), was identified as a potent mixed KCa2/3 channel inhibitor with an EC50 of 19 nM for KCa3.1 and 360 pM for KCa2.3, which affected KCa1.1 and Kv channels only at micromolar concentrations. The KCa3.1/KCa2-activator SKA-31 antagonized the 13b-blockade. In proliferation assays, 13b was not cytotoxic and reduced proliferation of 3T3 fibroblasts as well as caffeic acid. In isometric vessel myography, 13b increased contractions of porcine coronary arteries to serotonin and antagonized endothelium-derived hyperpolarization-mediated vasorelaxation to pharmacological KCa3.1/KCa2.3 activation. CONCLUSIONSSIGNIFICANCE: We identified the natural phenols, caffeic acid and resveratrol, the NSAID, flufenamic acid, and the polyphenol 13b as novel KCa3.1 inhibitors. The high potency of 13b with pan-activity on KCa3.1/KCa2 channels makes 13b a new pharmacological tool to manipulate inflammation and cancer growth through KCa3.1/KCa2 blockade and a promising template for new drug design.",
author = "Aida Olivan-Viguera and Valero, {Marta Sof{\'i}a} and Murillo, {Mar{\'i}a Divina} and Heike Wulff and Angel-Luis Garc{\'i}a-Ot{\'i}n and Jos{\'e}-Miguel Arbon{\'e}s-Mainar and Ralf K{\"o}hler",
year = "2013",
doi = "10.1371/journal.pone.0058614",
language = "English",
volume = "8",
pages = "e58614",
journal = "P L o S One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "3",

}

Olivan-Viguera, A, Valero, MS, Murillo, MD, Wulff, H, García-Otín, A-L, Arbonés-Mainar, J-M & Köhler, R 2013, 'Novel Phenolic Inhibitors of Small/Intermediate-Conductance Ca(2+)-Activated K(+) Channels, KCa3.1 and KCa2.3', P L o S One, bind 8, nr. 3, s. e58614. https://doi.org/10.1371/journal.pone.0058614

Novel Phenolic Inhibitors of Small/Intermediate-Conductance Ca(2+)-Activated K(+) Channels, KCa3.1 and KCa2.3. / Olivan-Viguera, Aida; Valero, Marta Sofía; Murillo, María Divina; Wulff, Heike; García-Otín, Angel-Luis; Arbonés-Mainar, José-Miguel; Köhler, Ralf.

I: P L o S One, Bind 8, Nr. 3, 2013, s. e58614.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Novel Phenolic Inhibitors of Small/Intermediate-Conductance Ca(2+)-Activated K(+) Channels, KCa3.1 and KCa2.3

AU - Olivan-Viguera, Aida

AU - Valero, Marta Sofía

AU - Murillo, María Divina

AU - Wulff, Heike

AU - García-Otín, Angel-Luis

AU - Arbonés-Mainar, José-Miguel

AU - Köhler, Ralf

PY - 2013

Y1 - 2013

N2 - BACKGROUND: KCa3.1 channels are calcium/calmodulin-regulated voltage-independent K(+) channels that produce membrane hyperpolarization and shape Ca(2+)-signaling and thereby physiological functions in epithelia, blood vessels, and white and red blood cells. Up-regulation of KCa3.1 is evident in fibrotic and inflamed tissues and some tumors rendering the channel a potential drug target. In the present study, we searched for novel potent small molecule inhibitors of KCa3.1 by testing a series of 20 selected natural and synthetic (poly)phenols, synthetic benzoic acids, and non-steroidal anti-inflammatory drugs (NSAIDs), with known cytoprotective, anti-inflammatory, and/or cytostatic activities. METHODOLOGYPRINCIPAL FINDINGS: In electrophysiological experiments, we identified the natural phenols, caffeic acid (EC50 1.3 µM) and resveratrol (EC50 10 µM) as KCa3.1 inhibitors with moderate potency. The phenols, vanillic acid, gallic acid, and hydroxytyrosol had weak or no blocking effects. Out of the NSAIDs, flufenamic acid was moderately potent (EC50 1.6 µM), followed by mesalamine (EC50≥10 µM). The synthetic fluoro-trivanillic ester, 13b ([3,5-bis[(3-fluoro-4-hydroxy-benzoyl)oxymethyl]phenyl]methyl 3-fluoro-4-hydroxy-benzoate), was identified as a potent mixed KCa2/3 channel inhibitor with an EC50 of 19 nM for KCa3.1 and 360 pM for KCa2.3, which affected KCa1.1 and Kv channels only at micromolar concentrations. The KCa3.1/KCa2-activator SKA-31 antagonized the 13b-blockade. In proliferation assays, 13b was not cytotoxic and reduced proliferation of 3T3 fibroblasts as well as caffeic acid. In isometric vessel myography, 13b increased contractions of porcine coronary arteries to serotonin and antagonized endothelium-derived hyperpolarization-mediated vasorelaxation to pharmacological KCa3.1/KCa2.3 activation. CONCLUSIONSSIGNIFICANCE: We identified the natural phenols, caffeic acid and resveratrol, the NSAID, flufenamic acid, and the polyphenol 13b as novel KCa3.1 inhibitors. The high potency of 13b with pan-activity on KCa3.1/KCa2 channels makes 13b a new pharmacological tool to manipulate inflammation and cancer growth through KCa3.1/KCa2 blockade and a promising template for new drug design.

AB - BACKGROUND: KCa3.1 channels are calcium/calmodulin-regulated voltage-independent K(+) channels that produce membrane hyperpolarization and shape Ca(2+)-signaling and thereby physiological functions in epithelia, blood vessels, and white and red blood cells. Up-regulation of KCa3.1 is evident in fibrotic and inflamed tissues and some tumors rendering the channel a potential drug target. In the present study, we searched for novel potent small molecule inhibitors of KCa3.1 by testing a series of 20 selected natural and synthetic (poly)phenols, synthetic benzoic acids, and non-steroidal anti-inflammatory drugs (NSAIDs), with known cytoprotective, anti-inflammatory, and/or cytostatic activities. METHODOLOGYPRINCIPAL FINDINGS: In electrophysiological experiments, we identified the natural phenols, caffeic acid (EC50 1.3 µM) and resveratrol (EC50 10 µM) as KCa3.1 inhibitors with moderate potency. The phenols, vanillic acid, gallic acid, and hydroxytyrosol had weak or no blocking effects. Out of the NSAIDs, flufenamic acid was moderately potent (EC50 1.6 µM), followed by mesalamine (EC50≥10 µM). The synthetic fluoro-trivanillic ester, 13b ([3,5-bis[(3-fluoro-4-hydroxy-benzoyl)oxymethyl]phenyl]methyl 3-fluoro-4-hydroxy-benzoate), was identified as a potent mixed KCa2/3 channel inhibitor with an EC50 of 19 nM for KCa3.1 and 360 pM for KCa2.3, which affected KCa1.1 and Kv channels only at micromolar concentrations. The KCa3.1/KCa2-activator SKA-31 antagonized the 13b-blockade. In proliferation assays, 13b was not cytotoxic and reduced proliferation of 3T3 fibroblasts as well as caffeic acid. In isometric vessel myography, 13b increased contractions of porcine coronary arteries to serotonin and antagonized endothelium-derived hyperpolarization-mediated vasorelaxation to pharmacological KCa3.1/KCa2.3 activation. CONCLUSIONSSIGNIFICANCE: We identified the natural phenols, caffeic acid and resveratrol, the NSAID, flufenamic acid, and the polyphenol 13b as novel KCa3.1 inhibitors. The high potency of 13b with pan-activity on KCa3.1/KCa2 channels makes 13b a new pharmacological tool to manipulate inflammation and cancer growth through KCa3.1/KCa2 blockade and a promising template for new drug design.

U2 - 10.1371/journal.pone.0058614

DO - 10.1371/journal.pone.0058614

M3 - Journal article

VL - 8

SP - e58614

JO - P L o S One

JF - P L o S One

SN - 1932-6203

IS - 3

ER -

Olivan-Viguera A, Valero MS, Murillo MD, Wulff H, García-Otín A-L, Arbonés-Mainar J-M et al. Novel Phenolic Inhibitors of Small/Intermediate-Conductance Ca(2+)-Activated K(+) Channels, KCa3.1 and KCa2.3. P L o S One. 2013;8(3):e58614. https://doi.org/10.1371/journal.pone.0058614