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IDENTIFICATION OF THE TARGETS REQUIRED FOR THE ANTI-TUMOR EFFECT OF CELECOXIB AND ITS NON-COX-2 INHIBITORY DERIVATIVE by Adel Kardosh A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (MOLECULAR MICROBIOLOGY AND IMMUNOLOGY) August 2007 Copyright 2007 Adel Kardosh
|Title||Identification of the targets required for the anti-tumor effect of celecoxib and its non-COX-2 inhibitory derivative|
|Degree||Doctor of Philosophy|
|Degree program||Molecular Microbiology & Immunology|
|School||Keck School of Medicine|
|Advisor (committee chair)||Schönthal, Axel H.|
|Advisor (committee member)||
Landolph, Joseph R.
Chen, Thomas C.
Hofman, Florence M.
|Abstract||The non-steroidal anti-inflammatory drug (NSAID) celecoxib (Celebrex®) was specifically developed as a selective cyclooxygenase-2 (COX-2) inhibitor. It is well established that COX-2 plays a role in carcinogenesis, and COX inhibitors have been shown to exert chemopreventive abilities. However, their usefulness for the treatment of established cancers is much less clear. It has emerged that celecoxib is unique, as it might have potential for the treatment of various types of cancer. In my work, I could demonstrate that celecoxib's anti-tumor properties are not related to its inhibition of COX-2. This is further evident by our development of 2,5-dimethyl-celecoxib (DMC), a close structural analog of celecoxib that lacks COX-2-inhibitory function, yet is able to potently mimic the anti-tumor effects of celecoxib in vitro and in vivo, indicating that these drugs exert their cytotoxic effects by affecting different targets other than COX-2.; We investigated a variety of tumors with varying expression levels of COX-2. We analyzed numerous parameters of intracellular signal transduction, cell cycle regulation, ER stress response, and cell death pathways. Our results demonstrate that both drugs are able to effectively inhibit tumor cell growth similarly in vitro and in vivo. They are able to block signal transduction by the mitogen-activated protein (MAP) kinase and the JAK/STAT pathway, two key proliferation pathways. They arrest cell cycle progression via the transcriptional down-regulation of cyclin A and cyclin B, which are two essential regulatory components of cyclin-dependent kinases (CDKs). Treatment with both drugs stimulates apoptosis via the specific downregulation of survivin expression, an anti-apoptotic protein, and stimulation of caspase-3 activity. In addition, we show that both drugs generate increased levels of intracellular calcium [Ca2+], and trigger the activation of the endoplasmic reticulum (ER) stress response as indicated by the ER stress-associated proteins GRP78/BiP, CHOP/GADD153, and caspase-4, which is followed by apoptotic cell death. In summary celecoxib and its non-coxib analog DMC rapidly induce ER stress, which leads to inhibition of tumor cell proliferation and induces apoptosis without theinvolvement of COX-2.; This work establishes that COX-2 is not relevant for the antitumor effects of these drugs and therefore proposes the possibility that DMC could be developed as a non-coxib alternative to celecoxib for anti-cancer purposes.|
|Keyword||celecoxib; Celebrex; NSAIDs; cell cycle; CDK; DMC; 2,5-dimethyl-celecoxib; survivin; apoptosis; ER Stress; CHOP; GRP78; SERCA; Caspase 4|
|Part of collection||University of Southern California dissertations and theses|
|Publisher (of the original version)||University of Southern California|
|Place of publication (of the original version)||Los Angeles, California|
|Publisher (of the digital version)||University of Southern California. Libraries|
|Legacy record ID||usctheses-m562|
|Repository name||Libraries, University of Southern California|
|Repository address||Los Angeles, California|
|Full text||IDENTIFICATION OF THE TARGETS REQUIRED FOR THE ANTI-TUMOR EFFECT OF CELECOXIB AND ITS NON-COX-2 INHIBITORY DERIVATIVE by Adel Kardosh A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (MOLECULAR MICROBIOLOGY AND IMMUNOLOGY) August 2007 Copyright 2007 Adel Kardosh|