Identification of acid-sensing ion channels in adenoid cystic carcinomas

Ye, Jinhai; Gao, Jun; Wu, Yunong; Hu, YeGang; Zhang, Chenping; Xu, Tian‐Le

doi:10.1016/j.bbrc.2007.02.061

Cited by 24 publications

(21 citation statements)

References 30 publications

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Section: Anti‐tumour and Anti‐metastasis Effects Of Amiloride Via Inhmentioning

confidence: 99%

“…Recent findings indicate that NHE‐induced reductions in pH e can give rise to tumour‐selective activation of acid‐sensing ion channels (ASICs) 41. ASICs, which belong to the ENaC superfamily, are predominantly found in neurons, but they are also being discovered in other cell types 41, 42. While their normal physiological functions are still being elucidated, one possibility is that functional expression of ASICs may help tumours adapt to the low‐pH e environments created through increased NHE activity 43.…”

Section: Anti‐tumour and Anti‐metastasis Effects Of Amiloride Via Inhmentioning

confidence: 99%

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Anti‐tumour/metastasis effects of the potassium‐sparing diuretic amiloride: An orally active anti‐cancer drug waiting for its call‐of‐duty?

Matthews

Ranson

Kelso

2011

Intl Journal of Cancer

122

108

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Amiloride.HCl is clinically used as an oral potassium-sparing diuretic, but multiple studies in biochemical, cellular and animal models have shown that the drug also possesses anti-tumour and anti-metastasis activities. The additional effects appear to arise through inhibition of two discrete targets: (i) the sodium-hydrogen exchanger 1 (NHE1), a membrane protein responsible for the characteristically low extracellular pH of tumours and (ii) the urokinase-type plasminogen activator (uPA), a serine protease mediator of cell migration, invasion and metastasis and well-known marker of poor prognosis in cancer. This minireview summarises for the first time the reported anti-tumour/metastasis effects of amiloride in experimental models, discusses the putative molecular mechanisms responsible for these effects and concludes by commenting on the pros and cons of trialling amiloride or one of its structural analogues as potential new anti-tumour/metastasis drugs.Amiloride.HCl is an orally administered potassium-sparing diuretic that has been used clinically for more than three decades. Ironically, its principal clinical use is not as a diuretic per se, since its diuretic effects are relatively mild. It is instead more commonly used in combination with thiazide (e.g., hydrochlorothiazide) or loop diuretics (e.g., frusemide) as an antikaliuretic in patients at risk of hypokalaemia during longterm treatment of hepatic cirrhosis and heart failure. It is also frequently used in combination with other diuretics to control K þ -levels when treating hypertension. 1 The drug is usually well tolerated at normal doses, shows low incidence of side effects and is contraindicated only in patients with impaired renal function, hyperkalaemia or acidosis. Hyperkalaemia and associated arrhythmias are the drug's most serious side effects but when used in combination with thiazide diuretics, the incidence of these is <1-2%. 2 Soon after its discovery, amiloride found additional nonclinical uses as a pharmacological tool for probing sodium transport in many types of tissues and cells-uses which continue to this day. 3 Multiple studies over the past three decades have demonstrated that amiloride also exhibits significant anti-tumour and anti-metastasis activities in biochemical, cellular and animal tumour models. This mini-review begins by summarising the reported anti-cancer activities of amiloride in experimental models, discusses its purported anti-cancer mechanisms of action and concludes by commenting on the possibility that amiloride or a close structural analogue might be worth trialling clinically as an orally administered anticancer drug, either as a stand-alone agent or in combination with current chemotherapeutics. Anti-Tumour and Anti-Metastasis Effects of Amiloride in Experimental ModelsReports of in vivo anti-tumour properties for amiloride first appeared in 1983 when it was shown to inhibit H6 hepatoma growth and DMA/J mammary adenocarcinoma growth in a dose-dependent fashion in Male A/J mice. Multiple injections (1 mg/kg) of ...

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Section: Anti‐tumour and Anti‐metastasis Effects Of Amiloride Via Inhmentioning

confidence: 99%

Section: Anti‐tumour and Anti‐metastasis Effects Of Amiloride Via Inhmentioning

confidence: 99%

Anti‐tumour/metastasis effects of the potassium‐sparing diuretic amiloride: An orally active anti‐cancer drug waiting for its call‐of‐duty?

Matthews

Ranson

Kelso

2011

Intl Journal of Cancer

122

108

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“…In general, much less is known about ASIC regulation than about that for ENaC. Despite this, there are a number of therapeutic opportunities afforded by manipulation of ASIC protein function or expression, including pain states, psychiatric disorders, neurodegenerative diseases, and cancer (218,412,421,428). The studies detailing the involvement of ASICs in these states come primarily from genetic knockout and inhibitor studies in animal models, though some human data are available.…”

Section: Asics As Therapeutic Targetsmentioning

confidence: 99%

“…Multiple studies have shown that ASICs and ENaCs are associated with cell migration and proliferation, even in nontumor cells (48,83,97,155,156). ENaC expression is also upregulated in melanoma cells (425), while in salivary gland carcinoma cells, an ASIC2/3 heteromeric conductance has been proposed to underlie a proton-gated current that was not present in normal salivary gland epithelia (428). To date, the best case for involvement of ASICs and ENaCs in tumors has come from studies of colonic and brain malignancies.…”

Section: Asics Enacs and Cancermentioning

confidence: 99%

ENaCs and ASICs as therapeutic targets

Qadri

Rooj

Fuller

2012

American Journal of Physiology-Cell Physiology

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The epithelial Na+channel (ENaC) and acid-sensitive ion channel (ASIC) branches of the ENaC/degenerin superfamily of cation channels have drawn increasing attention as potential therapeutic targets in a variety of diseases and conditions. Originally thought to be solely expressed in fluid absorptive epithelia and in neurons, it has become apparent that members of this family exhibit nearly ubiquitous expression. Therapeutic opportunities range from hypertension, due to the role of ENaC in maintaining whole body salt and water homeostasis, to anxiety disorders and pain associated with ASIC activity. As a physiologist intrigued by the fundamental mechanics of salt and water transport, it was natural that Dale Benos, to whom this series of reviews is dedicated, should have been at the forefront of research into the amiloride-sensitive sodium channel. The cloning of ENaC and subsequently the ASIC channels has revealed a far wider role for this channel family than was previously imagined. In this review, we will discuss the known and potential roles of ENaC and ASIC subunits in the wide variety of pathologies in which these channels have been implicated. Some of these, such as the role of ENaC in Liddle's syndrome are well established, others less so; however, all are related in that the fundamental defect is due to inappropriate channel activity.

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“…Salivary gland me as asis: In salivary gland carcinoma cells, an ASIC2/3 he eromeric conduc ance has been observed ha were absen in normal salivary gland epi helia [55]. To da e, in case of colonic and brain malignancies, he involvemen of ASICs were bes found.…”

Section: Pathophysiological Role Of Acid-sensing Ion Channelsmentioning

confidence: 99%

Acid Sensing Ion Channels (Asics): Potential Targets for the Discovery of Novel Therapeutics in Disease Management

Roy¹

2018

IJCBR

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INTRODUCTIONThe acid-sensing ion channels or ASICs form a distinc branch of he degenerin superfamily (ENaC/DEG) of sodium channels. A leas four ASIC genes have been identified in humans so far, numbered 1-4, wi h a number of splice varian s encoding a o al of nine unique pro eins [1][2][3][4][5][6][7][8][9]. The channels formed by he ASIC pro eins are basically pro on-ga ed cation channels, opening rapidly in he presence of ex racellular acid. All ASIC subuni consis s of a large ex racellular domain, 2 ransmembrane helices, and shor cy oplasmic N and C ermini. Functional ASICs are homo or he ero rimers of ASIC1a, ASIC1bASIC2a, ASIC2b, and/ or ASIC3 subuni s [10][11]. ASIC2b is no functional as homomultimer bu form functional he eromeric channels in combination wi h o her subuni s [12]. The activi y of ASIC4 channel has been de ec ed very limi ed ye . I may participa e in regulating he membrane availabili y of o her ASIC subuni s [13]. ASIC1a and ASIC3 are activa ed by an acidi y range (pH 7.0-6.0) observed in several acu e and chronic pain conditions. ASIC3 is particularly sensitive o lactic acidosis and hus is considered o be an impor an componen of acid induced pain [14].Corresponding author: Debendra Nath Roy, Department of Pharmacy, Faculty of Biological Science and Technology, Jessore University of Science and Technology, Jessore-7408, Bangladesh. Email: roydn009@gmail.com I has been noticed ha he activation of ASIC in neurons induce action po entials. The ex en and duration of he ASIC-media ed depolarization depends bo h on ASIC ampli ude activi y and he number of charges he channels ranspor during heir opening [15][16]. Among all o hers, ASIC3 is he mos sensitive o increases in pro on concen ration, wi h half-maximal pH activation is 6.4 [17]. ASIC2 is he leas sensitive, requiring exposure o pH 4.5 for halfmaximal activation. ASICs have been de ec ed hroughou he nervous sys em, specifically in areas of high synaptic densi y, localizing primarily o he soma and processes of neurons [18][19]. Their expression pattern has sugges ed ha hese channels play a role in sensory perception and various neural processes [20][21]. ASICs have widespread dis ribution o many regions in he nervous sys em including dorsal roo ganglia, cor ex, hippocampus, basal ganglia, amygdale, olfac ory bulb, cerebrum and elsewhere [22 -24]. In erestingly, ASICs are increasingly being de eced in nonneuronal settings including cancer cells [25], bone [26], in estinal and bladder epi helium cells and smoo h muscle [27][28][29][30]. Because ASICs are permeable o Na+, heir activation leads o membrane depolarization, hus inducing action po entials in neurons ASICs often have an activation effec on neurons. A s rong ASIC-media ed depolarization, however, can inhibi an already actively signaling neuron. ASIC1a has a small permeabili y for Ca2+ in addition o i s Na+ permeabili y, and some of i s cellular functions, as for example neurodegeneration after ischem- ABSTRACTAcid sensing ion channels (ASIC) are Na+ channels activa ed by ex ernal pro o...

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Identification of acid-sensing ion channels in adenoid cystic carcinomas

Cited by 24 publications

References 30 publications

Anti‐tumour/metastasis effects of the potassium‐sparing diuretic amiloride: An orally active anti‐cancer drug waiting for its call‐of‐duty?

Anti‐tumour/metastasis effects of the potassium‐sparing diuretic amiloride: An orally active anti‐cancer drug waiting for its call‐of‐duty?

ENaCs and ASICs as therapeutic targets

Acid Sensing Ion Channels (Asics): Potential Targets for the Discovery of Novel Therapeutics in Disease Management

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