Abstract
Phenytoin, a voltage-gated sodium channel (NaV channel) antagonist, reportedly inhibits arginine vasopressin (AVP) release from an isolated rat neurohypophysis. So far, it is uncertain whether phenytoin has a direct action on ectopic AVP-producing neuroendocrine tumors. We studied the effect of phenytoin on the release of copeptin, the C-terminal fragment of pro-AVP, and expression of AVP gene in the human small cell lung cancer cell line Lu-165. Cells were maintained in RPMI1640 medium with 10% fetal bovine serum and were used within the fifth passage. Copeptin was detected using a new sandwich immunoassay, and AVP mRNA levels were measured using real-time reverse transcription polymerase chain reaction. Treatment with phenytoin at a concentration of 25 µg/mL, but not at 5 or 10 µg/mL, had an inhibitory effect on copeptin levels in the medium at 48 h. At the same concentration, AVP mRNA levels in Lu-165 cells also decreased. Although a sodium challenge with added sodium at 20 mEq/L increased copeptin levels in the medium, a sodium challenge with added sodium at 10 and 20 mEq/L had no effect on AVP mRNA levels. Phenytoin at a concentration of 25 µg/mL suppressed copeptin levels in the medium under the sodium challenge with added sodium at 10 and 20 mEq/L. Phenytoin at a concentration of 25 µg/mL also decreased AVP mRNA levels in Lu-165 cells under the sodium challenge with added sodium at 10 mEq/L, but not at 20 mEq/L. Among five tested NaV channel subunits, NaV1.3 was highly expressed in Lu-165 cells. However, phenytoin significantly decreased NaV1.3 mRNA levels under the sodium challenge with added sodium at 10 and 20 mEq/L. These results suggest that Lu-165 cells are sensitive to phenytoin and sodium to control of AVP release and its gene expression. Phenytoin might have a direct action on ectopic AVP-producing tumors, suggesting the importance of NaV channels in AVP-producing neuroendocrine tumors.
Highlights
Phenytoin, a voltage-gated sodium channel (NaV channel) antagonist, is widely used as an anticonvulsant drug in epileptic patients [1]
We examined the effect of phenytoin with and without a sodium challenge on arginine vasopressin (AVP) mRNA expression and the release of copeptin, the C-terminal fragment of pro-AVP [10], in the human small cell lung cancer (SCLC) cell line Lu-165
The present study clearly demonstrates that Lu-165 cells expressed AVP mRNA and released copeptin and that a slightly greater than therapeutic dose of phenytoin reduced intracellular AVP mRNA levels and AVP surrogate copeptin concentrations in the medium of SCLC Lu-165 cells
Summary
A voltage-gated sodium channel (NaV channel) antagonist, is widely used as an anticonvulsant drug in epileptic patients [1]. It is well known that small cell lung cancer (SCLC), one of the most aggressive forms of cancer, is sometimes complicated with refractory hyponatremia because SCLC is one of neuroendocrine tumors with capability of producing AVP [4,5,6]. It is uncertain whether phenytoin has a direct action on ectopic AVP-producing SCLC cells. Notwithstanding, there is little evidence on the expression and role of NaV channels in AVP-producing SCLC cells. Lu-165 cells were previously established from a 50-year-old SCLC patient with SIADH [11]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
