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-celecoxib

Adel Kardosh, Encouse B. Golden, Peter Pyrko, Jasim Uddin, Florence M. Hofman, Thomas C. Chen, Stan G. Louie, Nicos A. Petasis, Axel H. Schönthal

Research output: Contribution to journalArticle

93 Citations (Scopus)

Abstract

The proteasome inhibitor bortezomib (Velcade) is known to trigger endoplasmic reticulum (ER) stress via the accumulation of obsolete and damaged proteins. The selective cyclooxygenase-2 (COX-2) inhibitor celecoxib (Celebrex) causes ER stress through a different mechanism (i.e., by causing leakage of calcium from the ER into the cytosol). Each of these two mechanisms has been implicated in the anticancer effects of the respective drug. We therefore investigated whether the combination of these two drugs would lead to further increased ER stress and would enhance their antitumor efficacy. With the use of human glioblastoma cell lines, we show that this is indeed the case. When combined, bortezomib and celecoxib triggered elevated expression of the ER stress markers GRP78/BiP and CHOP/ GADD153, caused activation of c-Jun NH 2-terminal kinase and ER stress-associated caspase-4, and greatly increased apoptotic cell death. Small interfering RNA-mediated knockdown of the protective ER chaperone GRP78/BiP further sensitized the tumor cells to killing by the drug combination. The contribution of celecoxib was independent of the inhibition of COX-2 because a non-coxib analogue of this drug, 2,5-dimethyl-celecoxib (DMC), faithfully and more potently mimicked these combination effects in vitro and in vivo. Taken together, our results show that combining bortezomib with celecoxib or DMC very potently triggers the ER stress response and results in greatly increased glioblastoma cytotoxicity. We propose that this novel drug combination should receive further evaluation as a potentially effective anticancer therapy.

Original languageEnglish (US)
Pages (from-to)843-851
Number of pages9
JournalCancer Research
Volume68
Issue number3
DOIs
StatePublished - Feb 1 2008
Externally publishedYes

Fingerprint

Celecoxib
Endoplasmic Reticulum Stress
Glioblastoma
Drug Combinations
Endoplasmic Reticulum
Proteasome Inhibitors
Cyclooxygenase 2 Inhibitors
Cyclooxygenase 2
Caspases
Pharmaceutical Preparations
Cytosol
Small Interfering RNA
2,5-dimethylcelecoxib
Bortezomib
Cell Death
Phosphotransferases
Calcium

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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-celecoxib. / Kardosh, Adel; Golden, Encouse B.; Pyrko, Peter; Uddin, Jasim; Hofman, Florence M.; Chen, Thomas C.; Louie, Stan G.; Petasis, Nicos A.; Schönthal, Axel H.

In: Cancer Research, Vol. 68, No. 3, 01.02.2008, p. 843-851.

Research output: Contribution to journalArticle

Kardosh, Adel ; Golden, Encouse B. ; Pyrko, Peter ; Uddin, Jasim ; Hofman, Florence M. ; Chen, Thomas C. ; Louie, Stan G. ; Petasis, Nicos A. ; Schönthal, Axel H. / 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-celecoxib. In: Cancer Research. 2008 ; Vol. 68, No. 3. pp. 843-851.
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AU - Golden, Encouse B.

AU - Pyrko, Peter

AU - Uddin, Jasim

AU - Hofman, Florence M.

AU - Chen, Thomas C.

AU - Louie, Stan G.

AU - Petasis, Nicos A.

AU - Schönthal, Axel H.

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