Abstract
Glioblastoma multiforme (GBM), a malignant brain tumor with a dismal prognosis, shows a high level of chemo- and radioresistance and, therefore, attempts to sensitize glioma cells are highly desired. Here, we addressed the question of whether artesunate (ART), a drug currently used in the treatment of malaria, enhances the killing response of glioblastoma cells to temozolomide (TMZ), which is the first-line therapeutic for GBM. We measured apoptosis, necrosis, autophagy and senescence, and the extent of DNA damage in glioblastoma cells. Further, we determined the tumor growth in nude mice. We show that ART enhances the killing effect of TMZ in glioblastoma cell lines and in glioblastoma stem-like cells. The DNA double-strand break level induced by TMZ was not clearly enhanced in the combined treatment regime. Also, we did not observe an attenuation of TMZ-induced autophagy, which is considered a survival mechanism. However, we observed a significant effect of ART on homologous recombination (HR) with downregulation of RAD51 protein expression and HR activity. Further, we found that ART is able to inhibit senescence induced by TMZ. Since HR and senescence are pro-survival mechanisms, its inhibition by ART appears to be a key node in enhancing the TMZ-induced killing response. Enhancement of the antitumor effect of TMZ by co-administration of ART was also observed in a mouse tumor model. In conclusion, the amelioration of TMZ-induced cell death upon ART co-treatment provides a rational basis for a combination regime of TMZ and ART in glioblastoma therapy.
Highlights
Treatment of the highly aggressively growing brain tumor glioblastoma multiforme is usually not effective, and patients have a dismal prognosis with a median survival of 14.6 months [1]
The induction of cell death at different times after the onset of treatment was determined by annexin V/PI staining
The mechanism of death of plasmodia is thought to result from iron-stimulated reactive oxygen species (ROS) production by ART in plasmodia host cells, the erythrocytes, and it has been concluded that membrane damage kills the microorganism in the host cells [29, 30]
Summary
Treatment of the highly aggressively growing brain tumor glioblastoma multiforme (glioma WHO grade IV; GBM) is usually not effective, and patients have a dismal prognosis with a median survival of 14.6 months [1]. Most probably extended gaps, are created during this faulty repair process, leading to blockage of DNA replication in the replication cycle, which in turn gives rise to DNA double-strand breaks (DSB) [7, 8]. These DSB trigger cell death by apoptosis, which we have shown is effectively induced in glioma cells as a late response following TMZ treatment [9]. Identifying agent(s) that inhibit pro-survival pathways such as autophagy and replicative senescence www.impactjournals.com/oncotarget and foster cell death pathways is highly desired and anticipated to support brain tumor therapy
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