New Alkyl-Lipid Blockers of SK3 Channels Reduce Cancer Cell Migration and Occurrence of Metastasis

A.      Girault; J.-P.      Haelters; M.      Potier-Cartereau; A.      Chantome; M.      Pinault; S.      Marionneau-Lambot; T.      Oullier; G.      Simon; H.      Couthon-Gourves; P.-A.      Jaffres; B.      Corbel; P.      Bougnoux; V.      Joulin; C.      Vandier

doi:10.2174/156800911798073069

Abstract

Edelfosine is an inhibitor of SK3 channel – mediated cell migration. However, this compound bears adverse in vivo side effects. Using cell SK3 dependent cell-migration assay, patch-clamp, 125I-apamin binding, and in vivo experiments we tested the ability of 15 lipid derivatives with chemical structures inspired from edelfosine to inhibit SK3 channels. Using a structure-activity relationship approach we identified an edelfosine analog named Ohmline (1-O-hexadecyl- 2-O-methyl-sn-glycero-3-lactose) with potent inhibitory effects on the SK3 channel. Its potency was greater for SK3 channels than for SK1 channels; it did not affect IKCa channels and only slightly but not significantly affected SK2 channels. This is the first SKCa channel blocker that can be used to discriminate between SK2 and SK1/SK3 channels and represents a useful tool to investigate the functional role of SK3 channels in peripheral tissues (that do not express SK1 channels). This compound, which acts with an IC50 of 300 nM, did not displace apamin from SKCa channels and had no effect on non-specific edelfosine targets such as protein kinase C (PKC), receptors for platelet activating factor (PAF) and lysophosphatidic acid (LPA), as well as non-cancerous cells. This is promising because the pitfalls associated with the use of edelfosine-like compounds have been that their effective and high concentrations are often cytotoxic due to their detergent-like character causing normal cell lysis. Finally, Ohmline reduced metastasis development in a mice model of tumor indicating that this compound could become a lead compound for the first class of lipid-antimetastatic agent.

Keywords: Edelfosine, glycero-lipid, KCa2.3, metastasis, migration, Small conductance calcium-activated K+, small hairpin RNA, Structure-activity relationship, Phospholipase C, Protein kinase C, Potential Calcium, Platelet Activating Factor, Multiplicity Of Infection