Low direct cytotoxicity and cytoprotective effects of nitric oxide releasing indomethacin

Wataru Tomisato; Ken Ichiro Tanaka; Shinji Tsutsumi; Tatsuya Hoshino; Kazumi Yokomizo; Keitarou Suzuki; Takashi Katsu; Tohru Mizushima; Tohru Mizushima

doi:10.1007/s10620-005-2963-4

Low direct cytotoxicity and cytoprotective effects of nitric oxide releasing indomethacin

Wataru Tomisato, Ken Ichiro Tanaka, Shinji Tsutsumi, Tatsuya Hoshino, Kazumi Yokomizo, Keitarou Suzuki, Takashi Katsu, Tohru Mizushima, Tohru Mizushima

School of Pharmacy

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

Abstract

Nitric oxide (NO) releasing non-steroidal anti-inflammatory drugs (NSAIDs) have shown a marked reduction of gastrointestinal side effects and we here examined the cytotoxicity of NCX 530 (NO-indomethacin). Under conditions where indomethacin clearly induced both necrosis and apoptosis, NCX 530 induced neither. NCX 530 protected cells from celecoxib-induced necrosis and apoptosis. NCX 530 partially suppressed celecoxib-dependent membrane permeabilization and an inhibitor for guanylate cyclase suppressed the cytoprotective effect of NCX 530 against celecoxib. In vivo, NCX 530 alone produced fewer gastric lesions in rats than did indomethacin. A combination of the oral administration of celecoxib together with the intraperitoneal administration of indomethacin, but not of NCX 530, clearly resulted in the production of gastric lesions. The low direct cytotoxicity and the cytoprotective effect of NCX 530 observed in vitro may also act in vivo, thus ensuring that NCX 530 is safe for use on the gastric mucosa.

Original language	English
Pages (from-to)	1927-1937
Number of pages	11
Journal	Digestive Diseases and Sciences
Volume	50
Issue number	10
DOIs	https://doi.org/10.1007/s10620-005-2963-4
Publication status	Published - 2005 Oct

Keywords

Cyclooxygenase
Direct cytotoxicity
Gastric lesion
Indomethacin
NO-NSAID
Selective cyclooxygenase-2 inhibitor

ASJC Scopus subject areas

Physiology
Gastroenterology

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10.1007/s10620-005-2963-4

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title = "Low direct cytotoxicity and cytoprotective effects of nitric oxide releasing indomethacin",

abstract = "Nitric oxide (NO) releasing non-steroidal anti-inflammatory drugs (NSAIDs) have shown a marked reduction of gastrointestinal side effects and we here examined the cytotoxicity of NCX 530 (NO-indomethacin). Under conditions where indomethacin clearly induced both necrosis and apoptosis, NCX 530 induced neither. NCX 530 protected cells from celecoxib-induced necrosis and apoptosis. NCX 530 partially suppressed celecoxib-dependent membrane permeabilization and an inhibitor for guanylate cyclase suppressed the cytoprotective effect of NCX 530 against celecoxib. In vivo, NCX 530 alone produced fewer gastric lesions in rats than did indomethacin. A combination of the oral administration of celecoxib together with the intraperitoneal administration of indomethacin, but not of NCX 530, clearly resulted in the production of gastric lesions. The low direct cytotoxicity and the cytoprotective effect of NCX 530 observed in vitro may also act in vivo, thus ensuring that NCX 530 is safe for use on the gastric mucosa.",

keywords = "Cyclooxygenase, Direct cytotoxicity, Gastric lesion, Indomethacin, NO-NSAID, Selective cyclooxygenase-2 inhibitor",

author = "Wataru Tomisato and Tanaka, {Ken Ichiro} and Shinji Tsutsumi and Tatsuya Hoshino and Kazumi Yokomizo and Keitarou Suzuki and Takashi Katsu and Tohru Mizushima and Tohru Mizushima",

note = "Funding Information: This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Health, Labour, and Welfare of Japan, as well as by the Suzuken Memorial Foundation, and the Japan Research Foundation for Clinical Pharmacology. We thank NicOx S. A. for providing indomethacin and NCX 530.",

year = "2005",

month = oct,

doi = "10.1007/s10620-005-2963-4",

language = "English",

volume = "50",

pages = "1927--1937",

journal = "Digestive Diseases and Sciences",

issn = "0163-2116",

publisher = "Springer New York",

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TY - JOUR

T1 - Low direct cytotoxicity and cytoprotective effects of nitric oxide releasing indomethacin

AU - Tomisato, Wataru

AU - Tanaka, Ken Ichiro

AU - Tsutsumi, Shinji

AU - Hoshino, Tatsuya

AU - Yokomizo, Kazumi

AU - Suzuki, Keitarou

AU - Katsu, Takashi

AU - Mizushima, Tohru

N1 - Funding Information: This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Health, Labour, and Welfare of Japan, as well as by the Suzuken Memorial Foundation, and the Japan Research Foundation for Clinical Pharmacology. We thank NicOx S. A. for providing indomethacin and NCX 530.

PY - 2005/10

Y1 - 2005/10

N2 - Nitric oxide (NO) releasing non-steroidal anti-inflammatory drugs (NSAIDs) have shown a marked reduction of gastrointestinal side effects and we here examined the cytotoxicity of NCX 530 (NO-indomethacin). Under conditions where indomethacin clearly induced both necrosis and apoptosis, NCX 530 induced neither. NCX 530 protected cells from celecoxib-induced necrosis and apoptosis. NCX 530 partially suppressed celecoxib-dependent membrane permeabilization and an inhibitor for guanylate cyclase suppressed the cytoprotective effect of NCX 530 against celecoxib. In vivo, NCX 530 alone produced fewer gastric lesions in rats than did indomethacin. A combination of the oral administration of celecoxib together with the intraperitoneal administration of indomethacin, but not of NCX 530, clearly resulted in the production of gastric lesions. The low direct cytotoxicity and the cytoprotective effect of NCX 530 observed in vitro may also act in vivo, thus ensuring that NCX 530 is safe for use on the gastric mucosa.

AB - Nitric oxide (NO) releasing non-steroidal anti-inflammatory drugs (NSAIDs) have shown a marked reduction of gastrointestinal side effects and we here examined the cytotoxicity of NCX 530 (NO-indomethacin). Under conditions where indomethacin clearly induced both necrosis and apoptosis, NCX 530 induced neither. NCX 530 protected cells from celecoxib-induced necrosis and apoptosis. NCX 530 partially suppressed celecoxib-dependent membrane permeabilization and an inhibitor for guanylate cyclase suppressed the cytoprotective effect of NCX 530 against celecoxib. In vivo, NCX 530 alone produced fewer gastric lesions in rats than did indomethacin. A combination of the oral administration of celecoxib together with the intraperitoneal administration of indomethacin, but not of NCX 530, clearly resulted in the production of gastric lesions. The low direct cytotoxicity and the cytoprotective effect of NCX 530 observed in vitro may also act in vivo, thus ensuring that NCX 530 is safe for use on the gastric mucosa.

KW - Cyclooxygenase

KW - Direct cytotoxicity

KW - Gastric lesion

KW - Indomethacin

KW - NO-NSAID

KW - Selective cyclooxygenase-2 inhibitor

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JO - Digestive Diseases and Sciences

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ER -

Low direct cytotoxicity and cytoprotective effects of nitric oxide releasing indomethacin

Abstract

Keywords

ASJC Scopus subject areas

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