Discovery and evaluation of nNav1.5 sodium channel blockers with potent cell invasion inhibitory activity in breast cancer cells. Issue 9 (15th May 2018)

• Record Type: Journal Article
• Authors: Dutta, Shilpa; Lopez Charcas, Osbaldo; Tanner, Samuel; Gradek, Frédéric; Driffort, Virginie; Roger, Sébastien; Selander, Katri; Velu, Sadanandan E.; Brouillette, Wayne
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 9(2018)
• Page Start: 2428
• Page End: 2436
• Publication Date: 2018-05-15
• Subjects: CDCl3 Deuterated chloroform -- CH2Cl2 Methylene dichloride -- 13C NMR Carbon-13 nuclear magnetic resonance -- CoMFA Comparative molecular field analysis -- CuBr.Me2S Copper bromide dimethyl sulfide -- DMEM Dulbecco's modified eagle medium -- DMSO Dimethyl sulfoxide -- 3D-QSAR 3-Dimensional quantitative structure activity relationship -- Et3N Triethylamine -- EtOAc Ethyl acetate -- ER Estrogen receptor -- FBS fetal bovine serum -- HER-2 Human epidermal growth receptor 2 -- 1H NMR Hydrogen-1 nuclear magnetic resonance -- IC50 Inhibition concentration at 50% -- INa Sodium currents -- MeOH Methanol -- MTS [3-(4, 5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] -- NaBH(OAc)3 Sodium triacetoxyborohydride -- nNav1.5 Neonatal Nav1.5 isoform -- Na2SO4 Sodium sulfate -- NH3 Ammonia -- NHE1 Na+/H+ exchanger type 1 -- NMR Nuclear magnetic resonance -- PBS Phosphate buffered saline -- pHi Intracellular pH -- ppm Parts per million -- PR Progesterone receptor -- PSS Physiological saline solution -- Rf Retention factor -- THF Tetrahydrofuran -- TMS Tetramethylsilane -- TLC Thin layer chromatography -- TTX Tetrodotoxin -- UV Ultraviolet -- VGSC Voltage-gated sodium channels; Breast cancer -- nNav1.5 -- Voltage-gated sodium channel -- Sodium current -- Cancer cell invasion -- Metastasis; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.04.003
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: Identified novel nNav 1.5 blockers that inhibit breast cancer cell invasion. Most active compound blocked nNav 1.5 currents by 50% at 1 μM. Most active compound displayed 30% reduction in cell invasion at 0.1 μM. Abstract: Voltage-gated sodium channels (VGSC) are a well-established drug target for anti-epileptic, anti-arrhythmic and pain medications due to their presence and the important roles that they play in excitable cells. Recently, their presence has been recognized in non-excitable cells such as cancer cells and their overexpression has been shown to be associated with metastatic behavior in a variety of human cancers. The neonatal isoform of the VGSC subtype, Nav 1.5 (nNav 1.5) is overexpressed in the highly aggressive human breast cancer cell line, MDA-MB-231. The activity of nNav 1.5 is known to promote the breast cancer cell invasion in vitro and metastasis in vivo, and its expression in primary mammary tumors has been associated with metastasis and patient death. Metastasis development is responsible for the high mortality of breast cancer and currently there is no treatment available to specifically prevent or inhibit breast cancer metastasis. In the present study, a 3D-QSAR model is used to assist the development of low micromolar small molecule VGSC blockers. Using this model, we have designed, synthesized and evaluated five small molecule compounds as blockers of nNav 1.5-dependent inward currents in whole-cell patch-clamp experiments in MDA-MB-231 cells. The most active compound identified from these studies blocked sodium currents by 34.9 ± 6.6% at 1 μM. This compound also inhibited the invasion of MDA-MB-231 cells by 30.3 ± 4.5% at 1 μM concentration without affecting the cell viability. The potent small molecule compounds presented here have the potential to be developed as drugs for breast cancer metastasis treatment.