Kusuhara H, Matsuyuki H, Matsuura M, Imayoshi T, Okumoto T, Matsui H
Research Laboratories, Yoshitomi Pharmaceutical Industries, Fukuoka, Japan.
Eur J Pharmacol. 1998 Nov 6;360(2-3):273-80. doi: 10.1016/s0014-2999(98)00679-7.
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to cause apoptosis in several cell lines including transformed chicken embryo fibroblasts and human colon cancer cells. We herein report the apoptotic effect of NSAIDs in a non-transformed cell line derived from the rat gastric mucosa, RGMI (rat gastric mucosa cell first). 1-[p-Chlorobenzoyl]-5-methoxy-2-methylindole-3-acetic acid (indomethacin) and sodium 2-(2,6-dichloroanilino)phenylacetate (sodium diclofenac), potent and non-selective inhibitors of cyclooxygenase, were found to induce DNA fragmentation in RGM1 cells in a time- and concentration-dependent manner. The expression of mRNA for cyclooxygenase-2 was hardly detected in the intact cells but was clearly enhanced when the cells were incubated with the two NSAIDs. In contrast, the expression of mRNA for cyclooxygenase-1 was constitutive and was never affected by NSAIDs. The effect of [3,4-di(4-methoxyphenyl)-5-isoxazolyl] acetic acid (mofezolac), a potent and highly preferential inhibitor of cyclooxygenase-1, and N-[2-(cyclohexyloxy)-4-nitrophenyl]methanesulphonamide (NS-398), a selective inhibitor of cyclooxygenase-2, on DNA fragmentation and cyclooxygenase-2 mRNA expression was weak compared to the effect of indomethacin or sodium diclofenac. The DNA fragmentation induced by sodium diclofenac was hardly affected by the exogenous addition of 16,16-dimethyl prostaglandin E2 but was inhibited by caspase inhibitors such as Ac-YVAD-CHO and Ac-DEVD-CHO. The present data provide the first evidence that NSAIDs, such as indomethacin and sodium diclofenac, cause apoptotic DNA fragmentation in cultured gastric mucosal cells, and also indicate the involvement of caspases rather than the inhibition of cellular prostaglandin synthesis in the apoptotic process.
非甾体抗炎药（NSAIDs）已被证明可在多种细胞系中诱导凋亡，包括转化的鸡胚成纤维细胞和人结肠癌细胞。我们在此报告NSAIDs对源自大鼠胃黏膜的非转化细胞系RGMI（大鼠胃黏膜细胞1）的凋亡作用。1- [对氯苯甲酰基] -5-甲氧基-2-甲基吲哚-3-乙酸（吲哚美辛）和2-（2,6-二氯苯胺基）苯乙酸钠（双氯芬酸钠），两种强效且非选择性的环氧化酶抑制剂，被发现可在RGM1细胞中以时间和浓度依赖性方式诱导DNA片段化。在完整细胞中几乎检测不到环氧化酶-2的mRNA表达，但当细胞与这两种NSAIDs一起孵育时，其表达明显增强。相比之下，环氧化酶-1的mRNA表达是组成性的，且从未受到NSAIDs的影响。[3,4-二（4-甲氧基苯基）-5-异恶唑基]乙酸（莫非佐辛）是一种强效且高度选择性的环氧化酶-1抑制剂，N- [2-（环己氧基）-4-硝基苯基]甲磺酰胺（NS-398）是一种环氧化酶-2的选择性抑制剂，与吲哚美辛或双氯芬酸钠相比，它们对DNA片段化和环氧化酶-2 mRNA表达的影响较弱。双氯芬酸钠诱导的DNA片段化几乎不受外源性添加的16,16-二甲基前列腺素E2的影响，但被半胱天冬酶抑制剂如Ac-YVAD-CHO和Ac-DEVD-CHO抑制。目前的数据提供了首个证据，表明吲哚美辛和双氯芬酸钠等NSAIDs可在培养的胃黏膜细胞中引起凋亡性DNA片段化，并且还表明在凋亡过程中半胱天冬酶参与其中，而非细胞前列腺素合成的抑制。
