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
- 30 December 2012
- journal article
- research article
- Published by Wiley in Journal of Neuroscience Research
- Vol. 91 (3), 393-406
- https://doi.org/10.1002/jnr.23169
Abstract
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.Keywords
This publication has 52 references indexed in Scilit:
- Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: an international consensus statementThe Lancet Oncology, 2009
- Aggravated Endoplasmic Reticulum Stress as a Basis for Enhanced Glioblastoma Cell Killing by Bortezomib in Combination with Celecoxib or Its Non-Coxib Analogue, 2,5-Dimethyl-CelecoxibCancer Research, 2008
- Endoplasmic reticulum stress: cell life and death decisionsJCI Insight, 2005
- Dimethyl-Celecoxib (DMC), a derivative of celecoxib that lacks cyclooxygenase-2-Inhibitory function, potently mimics the anti-tumor effects of celecoxib on burkitt’s lymphoma in vitro and in vivoCancer Biology & Therapy, 2005
- Celecoxib activates a novel mitochondrial apoptosis signaling pathwayThe FASEB Journal, 2003
- The cyclo-oxygenase-2 inhibitor celecoxib perturbs intracellular calcium by inhibiting endoplasmic reticulum Ca2+-ATPases: a plausible link with its anti-tumour effect and cardiovascular risksBiochemical Journal, 2002
- Inhibition of SERCA Ca2+ pumps by 2‐aminoethoxydiphenyl borate (2‐APB)JBIC Journal of Biological Inorganic Chemistry, 2002
- Mitochondria regulate Ca2+ wave initiation and inositol trisphosphate signal transduction in oligodendrocyte progenitorsJournal of Neurochemistry, 2002
- Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis.1995
- The endoplasmic reticulum and calcium storageBioEssays, 1990