Artesunate enhances the therapeutic response of glioma cells to temozolomide by inhibition of homologous recombination and senescence.
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.
Department of Toxicology, Medical Center of University of Mainz, D-55131 Mainz, Germany.
Nancy
N
Berte
Department of Toxicology, Medical Center of University of Mainz, D-55131 Mainz, Germany.
Stefanie
S
Lokan
Department of Toxicology, Medical Center of University of Mainz, D-55131 Mainz, Germany.
Marcus
M
Eich
Department of Neurosurgery, Medical Center of University of Mainz, D-55131 Mainz, Germany.
Ella
E
Kim
Department of Toxicology, Medical Center of University of Mainz, D-55131 Mainz, Germany.
Bernd
B
Kaina
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology; D000077332:Artesunate; D001932:Brain Neoplasms / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D005910:Glioma / Q000473:pathology*; D059765:Homologous Recombination / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
D037621:Artemisinins; D000077332:Artesunate; D003606:Dacarbazine; D000077204:Temozolomide
DNA repair; artesunate; glioblastoma; senescence; temozolomide