title: Caffeic acid phenethyl ester: Inhibition of metastatic cell behaviours via voltage-gated sodium channel in human breast cancer in vitro.
abstract: Caffeic acid phenethyl ester, derived from natural propolis, has been reported to have anti-cancer properties. Voltage-gated sodium channels are upregulated in many cancers where they promote metastatic cell behaviours, including invasiveness. We found that micromolar concentrations of caffeic acid phenethyl ester blocked voltage-gated sodium channel activity in several invasive cell lines from different cancers, including breast (MDA-MB-231 and MDA-MB-468), colon (SW620) and non-small cell lung cancer (H460). In the MDA-MB-231 cell line, which was adopted as a 'model', long-term (48 h) treatment with 18 μM caffeic acid phenethyl ester reduced the peak current density by 91% and shifted steady-state inactivation to more hyperpolarized potentials and slowed recovery from inactivation. The effects of long-term treatment were also dose-dependent, 1 μM caffeic acid phenethyl ester reducing current density by only 65%. The effects of caffeic acid phenethyl ester on metastatic cell behaviours were tested on the MDA-MB-231 cell line at a working concentration (1 μM) that did not affect proliferative activity. Lateral motility and Matrigel invasion were reduced by up to 14% and 51%, respectively. Co-treatment of caffeic acid phenethyl ester with tetrodotoxin suggested that the voltage-gated sodium channel inhibition played a significant intermediary role in these effects. We conclude, first, that caffeic acid phenethyl ester does possess anti-metastatic properties. Second, the voltage-gated sodium channels, commonly expressed in strongly metastatic cancers, are a novel target for caffeic acid phenethyl ester. Third, more generally, ion channel inhibition can be a significant mode of action of nutraceutical compounds.
authors.affiliation: Imperial College London, Department of Life Sciences, Neuroscience Solutions to Cancer Research Group, South Kensington Campus, London SW7 2AZ, UK. Electronic address: s.p.fraser@imperial.ac.uk.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Fraser
authors.affiliation: Imperial College London, Department of Life Sciences, Neuroscience Solutions to Cancer Research Group, South Kensington Campus, London SW7 2AZ, UK.
authors.forename: Faye
authors.initials: F
authors.lastname: Hemsley
authors.affiliation: Imperial College London, Department of Life Sciences, Neuroscience Solutions to Cancer Research Group, South Kensington Campus, London SW7 2AZ, UK; Biotechnology Research Centre (BRC), Cyprus International University, Haspolat, Lefkosa, North Cyprus, Mersin 10, Turkey.
authors.forename: Mustafa B A
authors.initials: MBA
authors.lastname: Djamgoz
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D002109:Caffeic Acids / Q000494:pharmacology*; D045744:Cell Line, Tumor; D055724:Electrophysiological Phenomena / Q000187:drug effects; D006801:Humans; D009362:Neoplasm Metastasis; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D002109:Caffeic Acids; D061566:Voltage-Gated Sodium Channels; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol
keywords: Breast; Cancer; Colon; Non-small cell lung; Voltage-gated sodium channel