Sulindac sulfide inhibits sarcoendoplasmic reticulum Ca2+ ATPase, induces endoplasmic reticulum stress response, and exerts toxicity in glioma cells: relevant similarities to and important differences from celecoxib.
Sulindac sulfide inhibits sarcoendoplasmic reticulum Ca2+ ATPase, induces endoplasmic reticulum stress response, and exerts toxicity in glioma cells: relevant similarities to and important differences from celecoxib.
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DOI：
10.1002/jnr.23169
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发表时间：
2013-03
影响因子：
4.2
通讯作者：
Grimaldi, M.
中科院分区：
文献类型：
--
作者：
White, M. C.;Johnson, G. G.;Zhang, W.;Hobrath, J. V.;Piazza, G. A.;Grimaldi, M.
恶性神经胶质瘤的生存预期较低，无论目前的治疗。非甾体抗炎药（NSAID）通过不依赖于环氧合酶（考克斯）抑制的机制防止细胞转化并减缓癌细胞生长。某些NSAID触发内质网应激反应（ERSR），如通过分子伴侣如GRP 78和C/EBP同源蛋白（CHOP）的上调所揭示的。虽然塞来昔布（CELE）抑制肌内质网Ca 2 + ATP酶（SERCA），已知其作用可诱导ERSR，但尚未报告舒林酸硫化物（SS）影响SERCA。在这里，我们研究了这两种药物对Ca 2+稳态，ERSR和胶质瘤细胞存活的影响。我们的研究结果表明，SS是一个可逆的抑制剂的SERCA和SS和CELE结合SERCA在其cyclopiazonic酸结合位点。此外，CELE从线粒体释放额外的Ca 2+。在神经胶质瘤细胞中，两种NSAIDS均上调GRP 78并激活ER相关的caspase-4和caspase-3。虽然只有CELE上调CHOP的表达，但CHOP诱导似乎与线粒体中毒有关。此外，在我们的实验中，CHOP诱导似乎与这些NSAIDS的神经胶质毒性无关。我们的数据表明，ERSR的激活是主要负责这些NSAIDS的神经胶质细胞毒性作用。由于SS具有良好的脑生物利用度，具有较低的考克斯-2抑制，并且没有线粒体效应，因此它代表了比CELE更有吸引力的通过ERSR活化实现胶质细胞毒性的分子候选物。
Malignant gliomas have low survival expectations regardless of current treatments. Nonsteroidal anti-inflammatory drugs (NSAIDs) prevent cell transformation and slow cancer cell growth by mechanisms independent of cyclooxygenase (COX) inhibition. Certain NSAIDs trigger the endoplasmic reticulum stress response (ERSR), as revealed by upregulation of molecular chaperones such as GRP78 and C/EBP homologous protein (CHOP). Although celecoxib (CELE) inhibits the sarcoendoplasmic reticulum Ca2+ ATPase (SERCA), an effect known to induce ERSR, sulindac sulfide (SS) has not been reported to affect SERCA. Here, we investigated these two drugs for their effects on Ca2+ homeostasis, ERSR, and glioma cell survival. Our findings indicate that SS is a reversible inhibitor of SERCA and that both SS and CELE bind SERCA at its cyclopiazonic acid binding site. Furthermore, CELE releases additional Ca2+ from the mitochondria. In glioma cells, both NSAIDS upregulate GRP78 and activate ER-associated caspase-4 and caspase-3. Although only CELE upregulates the expression of CHOP, it appears that CHOP induction could be associated with mitochondrial poisoning. In addition, CHOP induction appears to be uncorrelated with the gliotoxicity of these NSAIDS in our experiments. Our data suggest that activation of ERSR is primarily responsible for the gliotoxic effect of these NSAIDS. Because SS has good brain bioavailability, has lower COX-2 inhibition, and has no mitochondrial effects, it represents a more appealing molecular candidate than CELE to achieve gliotoxicity via activation of ERSR.
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影响因子：
4.7
作者：
Haak, LL;Grimaldi, M;Russell, JT
通讯作者：
Russell, JT
影响因子：
12.8
作者：
Kang, You Jung;Kim, In Young;Choi, Kyeong Sook
通讯作者：
Choi, Kyeong Sook
影响因子：
11.2
作者：
Jiang, Chen Chen;Chen, Li Hua;Hersey, Peter
通讯作者：
Hersey, Peter
影响因子：
3.6
作者：
Kardosh, A;Wang, WJ;Schönthal, AH
通讯作者：
Schönthal, AH
影响因子：
3.6
作者：
Kardosh, A;Blumenthal, M;Schönthal, AH
通讯作者：
Schönthal, AH