Targeting ER stress for malignant glioma therapy

UnrestrictedPoor chemosensitivity and the development of chemoresistance remain major obstacles to successful chemotherapy of malignant gliomas. Recently, a new goal has been set: changing malignant glioma from a deadly to a chronic disease. To this end a multidisciplinary approach to malignant glioma treatment has been proposed, in which surgery, radiotherapy and chemotherapy are combined in order to most benefit the patients. We identified endoplasmic reticulum (ER) as a novel target and outlined specific pathways within the ER stress response (ESR) that lead to malignant glioma cell death/apoptosis.; First, we report that ER chaperone GRP78 is significantly elevated in malignant glioma. Knockdown of GRP78 using siRNA in glioblastoma cell lines significantly lowers their resistance to temozolomide (TMZ), the chemotherapeutic agent of choice for treatment of malignant gliomas, as established by colony survival assays.; Second, we show that dimethyl celecoxib (DMC), an analog of celecoxib (Cxb) lacking its anti cox-2-inhibitory function, potently induces endoplasmic reticulum stress response (ESR) and subsequent apoptotic cell death in vitro and in vivo by modulating intracellular free calcium levels.; Third, we demonstrate that human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) cause efficient cell death in various malignant glioma cell lines in vitro via the potent stimulation of the ESR. Furthermore, we show that treatment of cells with PIs leads to aggresome formation and accumulation of polyubiquitinated proteins, implying proteasome inhibition. We also show that nelfinavir inhibits the growth of xenografted human malignant glioma, with concomitant induction of the pro-apoptotic ER stress marker CHOP.; In conclusion, we present a way to modify existing glioma therapy by modulating a protective ER chaperone, which we show protects from TMZ treatment. In addition, we demonstrate that Cxb and PIs are effective as single anti glioma agents in an in vitro setting through their potent induction of ESR pathways. Since both Cxb and PIs have been shown to have chemo and radiosensitizing potential, we propose that their ability to increase chemo and radiosensitivity of glioma cells should be investigated in further detail