Erastin sensitizes glioblastoma cells to temozolomide by restraining xCT and cystathionine-γ-lyase function.

Abstract

Glioblastoma multiforme (GBM) is one of the most common encephalic malignant tumors. Due to a high recurrence rate and a lack of effective treatments, the average survival rate remains low. Temozolomide (TMZ), a class of alkylating agent, is widely used as a first-line therapeutic drug during the adjuvant treatment for GBM patients. However, most patients exhibit a palpable resistance to TMZ treatment. Additionally, the underlying mechanism remains to be clarified. In this study, glutathione (GSH) and reactive oxygen species (ROS) levels were found to be closely associated with the sensitivity of GBM cells to TMZ. We also found that TMZ markedly induced xCT, the subunit of glutamate/cystine transporter system xc- expression, which together with the GSH synthesis was increased while the TMZ-inducible ROS level was decreased in GBM cells. In addition, the cystathionine γ-lyase (CTH) acivity, a key enzyme in the transsulfuration pathway was enhanced by TMZ, which insured a cysteine supply and GSH synthesis in a compensatory manner when xCT was blocked. Thus, the individual inhibition of xCT by siRNA and a pharmacological inhibitor (sulfasalazine) only partially inhibited GSH synthesis and moderately enhanced the GBM cell sensitivity to TMZ. However, the TMZ‑induced cytotoxicity was markedly increased along with a marked decrease in GSH levels as result of co-treatment with erastin, which inhibited cysteine uptake from xCT transporter and suppressed CTH activity, leading to impaired transformation from methionine to cysteine. In conclusion, to GBM therapy with a drug combination of TMZ and erastin may be beneficial.

• Authors: Liangyu Chen, Xinxing Li, Libo Liu, Bo Yu, Yixue Xue, Yunhui Liu
• Journal: Oncology reports (Oncol Rep) Vol. 33 Issue 3 Pg. 1465-74 (Mar 2015) ISSN: 1791-2431 [Electronic] Greece
• PMID: 25585997 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acid Transport System y+
• Antineoplastic Agents
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• Piperazines
• RNA, Small Interfering
• Reactive Oxygen Species
• SLC7A11 protein, human
• erastin
• Sulfasalazine
• Dacarbazine
• Cystathionine gamma-Lyase
• Glutathione
• Cysteine
• Temozolomide

Topics

• Amino Acid Transport System y+ (antagonists & inhibitors, genetics)
• Antineoplastic Agents (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Biological Transport (drug effects)
• Brain Neoplasms (drug therapy, pathology)
• Cell Line, Tumor
• Cell Survival
• Cystathionine gamma-Lyase (antagonists & inhibitors, genetics)
• Cysteine (metabolism)
• Dacarbazine (analogs & derivatives, pharmacology)
• Drug Resistance, Neoplasm (drug effects)
• Enzyme Activation
• Glioblastoma (drug therapy, pathology)
• Glutathione (biosynthesis, metabolism)
• Humans
• NF-E2-Related Factor 2 (genetics)
• Piperazines (pharmacology)
• RNA Interference
• RNA, Small Interfering
• Reactive Oxygen Species (metabolism)
• Sulfasalazine (pharmacology)
• Temozolomide