The SK3/K<sub>Ca</sub>2.3 potassium channel is a new cellular target for edelfosine

Potier, Marie‐Claude; Chantôme, Aurélie; Joulin, Virginie; Girault, Alban; Roger, Sébastien; Besson, Pierre; Jourdan, Marie-Lise; LeGuennec, Jean-Yves; Bougnoux, Philippe; Vandier, Christophe

doi:10.1111/j.1476-5381.2010.01044.x

Cited by 50 publications

(35 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Among them, the mechano-gated 2P domain potassium TREK-1 and TRAAK channels were found to be activated by lysoPAF. Edelfosine and ohmline were found to inhibit SK3 channel leading to a reduction of cancer cell migration Girault, et al, 2011;Potier, et al, 2011). This effect is dosedependent and with a selective inhibition of SK3-dependent cell migration below 1 µM.…”

Section: Accepted Manuscriptmentioning

confidence: 96%

“…(R)-N-(benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphtylamine, NS8593) but these compounds present side effects (neurotoxicity for apamin or a low selectivity of action for many heterocyclic-based compounds) . The evaluation of amphiphilic compounds, such as edelfosine, as potential modulators of SK3 channel was recently assessed Potier, et al, 2011). In vitro and in vivo evidence have shown that edelfosine induces apoptosis in a variety of tumor cells when used at the 6-10 µM range (Gajate, Fonteriz, et al, 2000;Mollinedo, et al, 1997), which corresponds to the concentration reached in plasma in animal model studies (EstellaHermoso de Mendoza, et al, 2009;.…”

Section: Accepted M Manuscriptmentioning

confidence: 96%

See 1 more Smart Citation

Alkyl ether lipids, ion channels and lipid raft reorganization in cancer therapy

Jaffrès

Gajate

Bouchet

et al. 2016

Pharmacology & Therapeutics

View full text Add to dashboard Cite

Synthetic alkyl lipids, such as the ether lipids edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) and ohmline (1-O-hexadecyl-2-O-methyl-rac-glycero-3-β-lactose), are forming a class of antitumor agents that target cell membranes to induce apoptosis and to decrease cell migration/invasion, leading to the inhibition of tumor and metastasis development. In this review, we present the structure-activity relationship of edelfosine and ohmline, and we point out differences and similarities between these two amphiphilic compounds. We also discuss the mechanisms of action of these synthetic alkyl ether lipids (involving, among other structures and molecules, membrane domains, Fas/CD95 death receptor signaling, and ion channels), and highlight a key role for lipid rafts in the underlying process. The reorganization of lipid raft membrane domains induced by these alkyl lipids affects the function of death receptors and ion channels, thus leading to apoptosis and/or inhibition of cancer cell migration. The possible therapeutic use of these alkyl lipids and the clinical perspectives for these lipids in prevention or/and treatment of tumor development and metastasis are also discussed.

show abstract

Section: Accepted Manuscriptmentioning

confidence: 96%

Section: Accepted M Manuscriptmentioning

confidence: 96%

Alkyl ether lipids, ion channels and lipid raft reorganization in cancer therapy

Jaffrès

Gajate

Bouchet

et al. 2016

Pharmacology & Therapeutics

View full text Add to dashboard Cite

show abstract

“…(ii) Translation of findings from xenograft models to the clinical situation is even more difficult, particularly in the case of high-grade glioma, because of obvious differences in the tumour microenvironment and the growth behaviour of the malignant cells in vivo [38]. In this scenario, the xenograft model will underestimate additional modes of drug action, such as inhibition of migration and invasion and antiangiogenic effects [39-42]. However, up to now the use of more appropriate preclinical models for the evaluation of the efficacy of combined treatment approaches with radiotherapy in vivo , e.g.…”

Section: Discussionmentioning

confidence: 99%

Effects of ionizing radiation in combination with Erufosine on T98G glioblastoma xenograft tumours: a study in NMRI nu/nu mice

et al. 2012

View full text Add to dashboard Cite

BackgroundErufosine is a promising anticancer drug that increases the efficacy of radiotherapy in glioblastoma cell lines in vitro. Moreover, treatment of nude mice with repeated intraperitoneal or subcutaneous injections of Erufosine is well tolerated and yields drug concentrations in the brain tissue that are higher than the concentrations required for cytotoxic drug effects on glioblastoma cell lines in vitro.MethodsIn the present study we aimed to evaluate the effects of a combined treatment with radiotherapy and Erufosine on growth and local control of T98G subcutaneous glioblastoma xenograft-tumours in NMRI nu/nu mice.ResultsWe show that repeated intraperitoneal injections of Erufosine resulted in a significant drug accumulation in T98G xenograft tumours on NMRI nu/nu mice. Moreover, short-term treatment with 5 intraperitoneal Erufosine injections caused a transient decrease in the growth of T98G tumours without radiotherapy. Furthermore, an increased radiation-induced growth delay of T98G xenograft tumours was observed when fractionated irradiation was combined with short-term Erufosine-treatment. However, no beneficial drug effects on fractionated radiotherapy in terms of local tumour control were observed.ConclusionsWe conclude that short-term treatment with Erufosine is not sufficient to significantly improve local control in combination with radiotherapy in T98G glioblastoma xenograft tumours. Further studies are needed to evaluate efficacy of extended drug treatment schedules.

show abstract

“…We have recently shown that edelfosine (26) (a known antitumorogenic compound) modulates SK3 function at low concentrations (1 μM) [130]. At this concentration, edelfosine had no effect on IKCa, but its effects on SKCa subtypes have yet to be studied.…”

Section: Modulation Of Skca Channels With Amphiphilesmentioning

confidence: 99%

Targeting SKCa Channels in Cancer: Potential New Therapeutic Approaches

Girault¹,

Haelters²,

Potier-Cartereau³

et al. 2012

CMC

View full text Add to dashboard Cite

Many studies have reported changes in potassium channel expression in many cancers and the involvement of these channels in various stages of cancer progression. By contrast, data concerning SKCa channels (small conductance calcium-activated potassium channels) have only recently become available. This review aims i) to present the structure and physiology of SKCa channels, ii) to provide an overview of published data concerning the SKCa proteins produced in tumor cells, and, whenever possible, the biological function assigned to them and iii) to review previous and novel modulators of SKCa channels. SKCa channels are activated by low concentrations of intracellular calcium and consist of homo- or heteromeric assemblies of α-subunits named SK1, SK2 and SK3. SK2-3 channels are expressed in tumors and have been assigned a biological function in cancer cells: the enhancement of cell proliferation and cell migration by hijacking the functions of SK2 and SK3 channels, respectively. Two major classes of SKCa modulators have been described: toxins (apamin) and small synthetic molecules. Most SKCa blockers are pore blockers, but some modify the calcium sensitivity of SKCa channels without interacting with the apamin binding site. In this review, we present edelfosine and ohmline as atypical anticancer agents and novel SK3 inhibitors. Edelfosine and ohmline are synthetic alkyl-lipids with structures different from all previously described SKCa modulators. They should pave the way for the development of a new class of migration-targeted anticancer agents. We believe that such blockers have potential for use in the prevention or treatment of metastasis.

show abstract

The SK3/K_Ca2.3 potassium channel is a new cellular target for edelfosine

Cited by 50 publications

References 51 publications

Alkyl ether lipids, ion channels and lipid raft reorganization in cancer therapy

Alkyl ether lipids, ion channels and lipid raft reorganization in cancer therapy

Effects of ionizing radiation in combination with Erufosine on T98G glioblastoma xenograft tumours: a study in NMRI nu/nu mice

Targeting SKCa Channels in Cancer: Potential New Therapeutic Approaches

Contact Info

Product

Resources

About

The SK3/KCa2.3 potassium channel is a new cellular target for edelfosine

Cited by 50 publications

References 51 publications

Alkyl ether lipids, ion channels and lipid raft reorganization in cancer therapy

Alkyl ether lipids, ion channels and lipid raft reorganization in cancer therapy

Effects of ionizing radiation in combination with Erufosine on T98G glioblastoma xenograft tumours: a study in NMRI nu/nu mice

Targeting SKCa Channels in Cancer: Potential New Therapeutic Approaches

Contact Info

Product

Resources

About

The SK3/K_Ca2.3 potassium channel is a new cellular target for edelfosine