Resveratrol Enhances Temozolomide Efficacy in Glioblastoma Cells through Downregulated MGMT and Negative Regulators-Related STAT3 Inactivation

• Published in: International journal of molecular sciences Vol. 24; no. 11; p. 9453
• Main Authors: Wu, Moli, Song, Danyang, Li, Hui, Ahmad, Nisar, Xu, Hong, Yang, Xiaobo, Wang, Qian, Cheng, Xiaoxin, Deng, Sa, Shu, Xiaohong
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 29.05.2023; MDPI
• Subjects: Alkylation; Antineoplastic Agents, Alkylating - pharmacology; Antineoplastic Agents, Alkylating - therapeutic use; Apoptosis; Brain; Brain cancer; Brain Neoplasms - drug therapy; Brain Neoplasms - genetics; Cancer; Cell adhesion & migration; Cell Line, Tumor; Cell proliferation; Chemoresistance; Chemotherapy; Cholecystokinin; DNA methyltransferase; DNA Modification Methylases - genetics; DNA Repair Enzymes - genetics; Down-regulation; Drug Resistance, Neoplasm; Drug therapy; Flow cytometry; Glioblastoma; Glioblastoma - pathology; Glioblastoma cells; Glioblastoma multiforme; Humans; Janus kinase 2; Methylguanine; MGMT; Molecular Chaperones - pharmacology; Molecular modelling; O6-methylguanine-DNA methyltransferase; Protein Inhibitors of Activated STAT; Resveratrol; Resveratrol - pharmacology; Resveratrol - therapeutic use; SHP-1 protein; STAT3; STAT3 negative regulators; Stat3 protein; STAT3 Transcription Factor - metabolism; Suppressor of Cytokine Signaling Proteins - metabolism; Temozolomide; Temozolomide - pharmacology; Temozolomide - therapeutic use; Tumors; China; temozolomide; STAT3 negative regulators; glioblastoma; MGMT; resveratrol; STAT3
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24119453

Chemoresistance blunts the efficacy of temozolomide (TMZ) in the treatment of glioblastoma (GBM). Elevated levels of O6-methylguanine-DNA methyltransferase (MGMT) and activation of signal transducer and of transcription 3 (STAT3) have been reported to correlate with GBM resistance to alkylator chemotherapy. Resveratrol (Res) inhibits tumor growth and improves drug chemosensitivity by targeting STAT3 signaling. Whether the combined therapy of TMZ and Res could enhance chemosensitivity against GBM cells and the underlying molecular mechanism remains to be determined. In this study, Res was found to effectively improve chemosensitivities of different GBM cells to TMZ, which was evaluated by CCK-8, flow cytometry, and cell migration assay. The combined use of Res and TMZ downregulated STAT3 activity and STAT3-regulated gene products, thus inhibited cell proliferation and migration, as well as induced apoptosis, accompanied by increased levels of its negative regulators: PIAS3, SHP1, SHP2, and SOCS3. More importantly, a combination therapy of Res and TMZ reversed TMZ resistance of LN428 cells, which could be related to decreased MGMT and STAT3 levels. Furthermore, the JAK2-specific inhibitor AG490 was used to demonstrate that a reduced MGMT level was mediated by STAT3 inactivation. Taken together, Res inhibited STAT3 signaling through modulation of PIAS3, SHP1, SHP2, and SOCS3, thereby attenuating tumor growth and increasing sensitivity to TMZ. Therefore, Res is an ideal candidate to be used in TMZ combined chemotherapy for GBM.