Potent inhibition by ropivacaine of metastatic colon cancer SW620 cell invasion and NaV1.5 channel function.
BACKGROUND
Metastatic breast and colon cancer cells express neonatal and adult splice variants of NaV1.5 voltage-activated Na(+) channels (VASCs). Block of VASCs inhibits cell invasion. Local anaesthetics used during surgical tumour excision inhibit VASC activity on nociceptive neurones providing regional anaesthesia. Inhibition of VASCs on circulating metastatic cancer cells may also be beneficial during the perioperative period. However, ropivacaine, frequently used to provide analgesia during tumour resection, has not been tested on colon cancer cell VASC function or invasion.


METHODS
We used reverse transcription-polymerase chain reaction and sequencing to identify NaV1.5 variants in the SW620 metastatic colon cancer cell line. Recombinant adult and neonatal NaV1.5 variants were expressed in human embryonic kidney cells. Voltage-clamp recordings and invasion assays were used to examine the effects of ropivacaine on recombinant NaV1.5 channels and the metastatic potential of SW620 cells, respectively.


RESULTS
SW620 cells expressed adult and neonatal NaV1.5 variants, which had similar steady-state inactivation profiles, but distinctive activation curves with the neonatal variant having a V1/2 of activation 7.8 mV more depolarized than the adult variant. Ropivacaine caused a concentration-dependent block of both NaV1.5 variants, with IC50 values of 2.5 and 3.9 µM, respectively. However, the reduction in available steady-state current was selective for neonatal NaV1.5 channels. Ropivacaine inhibited SW620 invasion, with a potency similar to that of inhibition of NaV1.5 channels (3.8 µM).


CONCLUSIONS
Ropivacaine is a potent inhibitor of both NaV1.5 channel activity and metastatic colon cancer cell invasion, which may be beneficial during surgical colon cancer excision.
The Institute of Academic Anaesthesia, Division of Neuroscience, Medical Research Institute Mailbox 8, Ninewells Hospital, University of Dundee, Dundee DD1 9SY, UK.
D T
DT
Baptista-Hon
The Institute of Academic Anaesthesia, Division of Neuroscience, Medical Research Institute Mailbox 8, Ninewells Hospital, University of Dundee, Dundee DD1 9SY, UK.
F M
FM
Robertson
The Institute of Academic Anaesthesia, Division of Neuroscience, Medical Research Institute Mailbox 8, Ninewells Hospital, University of Dundee, Dundee DD1 9SY, UK.
G B
GB
Robertson
The Institute of Academic Anaesthesia, Division of Neuroscience, Medical Research Institute Mailbox 8, Ninewells Hospital, University of Dundee, Dundee DD1 9SY, UK.
S J
SJ
Owen
The Institute of Academic Anaesthesia, Division of Neuroscience, Medical Research Institute Mailbox 8, Ninewells Hospital, University of Dundee, Dundee DD1 9SY, UK.
G W
GW
Rogers
The Institute of Academic Anaesthesia, Division of Neuroscience, Medical Research Institute Mailbox 8, Ninewells Hospital, University of Dundee, Dundee DD1 9SY, UK.
E L
EL
Lydon
Department of Pharmacology and Physiology, The George Washington University, 2300 Eye Street NW, Washington, DC 20037, USA.
N H
NH
Lee
The Institute of Academic Anaesthesia, Division of Neuroscience, Medical Research Institute Mailbox 8, Ninewells Hospital, University of Dundee, Dundee DD1 9SY, UK Department of Pharmacology and Physiology, The George Washington University, 2300 Eye Street NW, Washington, DC 20037, USA t.g.hales@dundee.ac.uk.
T G
TG
Hales
D000328:Adult; D000367:Age Factors; D000577:Amides / Q000008:administration & dosage / Q000494:pharmacology*; D000779:Anesthetics, Local / Q000008:administration & dosage / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D003094:Collagen; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D055724:Electrophysiological Phenomena / Q000187:drug effects; D006801:Humans; D007231:Infant, Newborn; D007797:Laminin; D008012:Lidocaine / Q000494:pharmacology; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000187:drug effects* / Q000502:physiology; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D018408:Patch-Clamp Techniques; D011509:Proteoglycans; D000077212:Ropivacaine
D000577:Amides; D000779:Anesthetics, Local; D004338:Drug Combinations; D007797:Laminin; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009363:Neoplasm Proteins; D011509:Proteoglycans; C568320:SCN5A protein, human; C059485:matrigel; D000077212:Ropivacaine; D003094:Collagen; D008012:Lidocaine
colorectal cancer; electrophysiology; ion channels; local anaesthetics