Temozolomide toxicity operates in a xCT/SLC7a11 dependent manner and is fostered by ferroptosis.
The glutamate exchanger xCT (SLC7a11) is causally linked with the malignancy grade of brain tumors and represents a key player in glutamate, cystine and glutathione metabolism. Although blocking xCT is not cytotoxic for brain tumors, xCT inhibition disrupts the neurodegenerative and microenvironment-toxifying activity of gliomas. Here, we report on the use of various xCT inhibitors as single modal drugs and in combination with the autophagy-inducing standard chemotherapeutic agent temozolomide (Temodal/Temcad®, TMZ). xCT overexpressing cells (xCTOE) are more resistant to the FDA and EMA approved drug sulfasalazine (Azulfidine/Salazopyrin/Sulazine®, SAS) and RNAi-mediated xCT knock down (xCTKD) in gliomas increases the susceptibility towards SAS in rodent gliomas. In human gliomas, challenged xCT expression had no impact on SAS-induced cytotoxicity. Noteworthy, other xCT inhibitors such as erastin and sorafenib showed enhanced efficacy on xCTKD gliomas. In contrast, cytotoxic action of TMZ operates independently from xCT expression levels on rodent gliomas. Human glioma cells with silenced xCT expression display higher vulnerability towards TMZ alone as well as towards combined TMZ and SAS. Hence, we tested the partial xCT blockers and ferroptosis inducing agents erastin and sorafenib (Nexavar®, FDA and EMA-approved drug for lung cancer). Noteworthy, xCTOE gliomas withstand erastin and sorafenib-induced cell death in a concentration-dependent manner, whereas siRNA-mediated xCT knock down increased susceptibility towards erastin and sorafenib. TMZ efficacy can be potentiated when combined with erastin, however not by sorafenib. Moreover, gliomas with high xCT expression are more vulnerable towards combinatorial treatment with erastin-temozolomide. These results disclose that ferroptosis inducers are valid compounds for potentiating the frontline therapeutic agent temozolomide in a multitoxic approach.
Translational Cell Biology & Neurooncology Laboratory, Department of Neurosurgery, Universitätsklinikum Erlangen, Medical School of The Friedrich Alexander University of Erlangen-Nürnberg (FAU), Schwabachanlage 6 (Kopfklinik), Germany.
Tina
T
Sehm
Department of Pediatrics and Adolescent Medicine, Universitätsklinikum Erlangen, Medical School of The Friedrich Alexander University of Erlangen-Nürnberg (FAU), Germany.
Manfred
M
Rauh
Department of Spinal Colum Therapies, Kliniken Dr. Erler, Nürnberg, Germany.
Kurt
K
Wiendieck
Translational Cell Biology & Neurooncology Laboratory, Department of Neurosurgery, Universitätsklinikum Erlangen, Medical School of The Friedrich Alexander University of Erlangen-Nürnberg (FAU), Schwabachanlage 6 (Kopfklinik), Germany.
Michael
M
Buchfelder
Translational Cell Biology & Neurooncology Laboratory, Department of Neurosurgery, Universitätsklinikum Erlangen, Medical School of The Friedrich Alexander University of Erlangen-Nürnberg (FAU), Schwabachanlage 6 (Kopfklinik), Germany.
IIker Y
IY
Eyüpoglu
Translational Cell Biology & Neurooncology Laboratory, Department of Neurosurgery, Universitätsklinikum Erlangen, Medical School of The Friedrich Alexander University of Erlangen-Nürnberg (FAU), Schwabachanlage 6 (Kopfklinik), Germany.|BiMECON Ent. Berlin, Germany.
Nicolai E
NE
Savaskan
D027182:Amino Acid Transport System y+ / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001253:Astrocytes / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004357:Drug Synergism; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D005910:Glioma / Q000378:metabolism; D006801:Humans; D051379:Mice; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D000077157:Sorafenib; D000077204:Temozolomide
D027182:Amino Acid Transport System y+; D018906:Antineoplastic Agents, Alkylating; D010671:Phenylurea Compounds; D010879:Piperazines; C118895:SLC7A11 protein, human; C477224:erastin; D009536:Niacinamide; D003606:Dacarbazine; D000077157:Sorafenib; D000077204:Temozolomide
apoptosis; brain tumor; cell death; ferroptosis; glioma niche