Version 1
: Received: 10 September 2024 / Approved: 10 September 2024 / Online: 10 September 2024 (09:50:35 CEST)
How to cite:
Jamali, F.; Lan, K.; Daniel, P.; Petrecca, K.; Sabri, S.; ABDULKARIM, B. Synergistic Dual Targeting of Thioredoxin and Glutathione Systems Irrespective of p53 in Glioblastoma Stem Cells. Preprints2024, 2024090790. https://doi.org/10.20944/preprints202409.0790.v1
Jamali, F.; Lan, K.; Daniel, P.; Petrecca, K.; Sabri, S.; ABDULKARIM, B. Synergistic Dual Targeting of Thioredoxin and Glutathione Systems Irrespective of p53 in Glioblastoma Stem Cells . Preprints 2024, 2024090790. https://doi.org/10.20944/preprints202409.0790.v1
Jamali, F.; Lan, K.; Daniel, P.; Petrecca, K.; Sabri, S.; ABDULKARIM, B. Synergistic Dual Targeting of Thioredoxin and Glutathione Systems Irrespective of p53 in Glioblastoma Stem Cells. Preprints2024, 2024090790. https://doi.org/10.20944/preprints202409.0790.v1
APA Style
Jamali, F., Lan, K., Daniel, P., Petrecca, K., Sabri, S., & ABDULKARIM, B. (2024). Synergistic Dual Targeting of Thioredoxin and Glutathione Systems Irrespective of p53 in Glioblastoma Stem Cells<strong> </strong>. Preprints. https://doi.org/10.20944/preprints202409.0790.v1
Chicago/Turabian Style
Jamali, F., Siham Sabri and BASSAM ABDULKARIM. 2024 "Synergistic Dual Targeting of Thioredoxin and Glutathione Systems Irrespective of p53 in Glioblastoma Stem Cells<strong> </strong>" Preprints. https://doi.org/10.20944/preprints202409.0790.v1
Abstract
Glioblastoma (GBM) is an incurable primary brain cancer characterized by increased reactive oxygen species (ROS) production. The redox-sensitive tumor suppressor gene TP53, wildtype (wt) for 70% of patients, regulates redox homeostasis. Glioblastoma stem cells (GSCs) increase thioredoxin (Trx) and glutathione (GSH) antioxidant systems as survival redox-adaptive mechanisms to maintain ROS below the cytotoxic threshold. Auranofin, an FDA-approved anti-rheumatoid drug, inhibits thioredoxin reductase 1 (TrxR1). L-buthionine sulfoximine (L-BSO) and the natural product piperlongumine (PPL) inhibit the GSH system. We evaluated the cytotoxic effects of Auranofin alone and in combination with L-BSO or PPL in GBM cell lines and GSCs with known TP53 status. The Cancer Genome Atlas/GBM analysis revealed a significant positive correlation between wtp53 and TrxR1 expression in GBM. Auranofin induced ROS-dependent cytotoxicity within a micromolar range in GSCs. Auranofin decreased TrxR1 expression, AKT(Ser-473) phosphorylation, increased p53, p21 and PARP-1 apoptotic cleavage in wtp53-GSCs, while mutant-p53 was decreased in a mutant-p53 GSC line. p53-knockdown in a wtp53-GSC line decreased TrxR1 expression and significantly increased sensitivity to auranofin, suggesting the role of wtp53 as a negative redox-sensitive mechanism in response to auranofin in GSCs. Auranofin and L-BSO combination synergistically increased ROS, decreased IC50s and induced long-term cytotoxicity irrespective of p53 in GBM cell lines and GSCs. Intriguingly, Auranofin increased expression of glutathione S-transferase pi-1 (GSTP-1), a target of PPL. Combination of auranofin with PPL synergistically decreased IC50s to a nanomolar range in GSCs, supporting the potential to repurpose auranofin and PPL in GBM.
Keywords
Glioblastoma;Glioblastoma stem cells (GSCs); Auranofin; thioredoxin reductase; oxidative stress; glutathione (GSH); reactive oxygen species (ROS); piperlongumine, antioxidant; drug repurposing.
Subject
Biology and Life Sciences, Life Sciences
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
