mTOR inhibition downregulates glucose-6-phosphate dehydrogenase and induces ROS-dependent death in T-cell acute lymphoblastic leukemia cells

Silic-Benussi, Micol; Sharova, Evgenyia; Ciccarese, Francesco; Cavallari, Ilaria; Raimondi, Vittoria; Urso, Loredana; Corradin, Alberto; Kotler, Harel; Scattolin, Gloria; Buldini, Barbara; Francescato, Samuela; Basso, Giuseppe; Minuzzo, Sonia; Indraccolo, Stefano; D’Agostino, Donna M.; Ciminale, Vincenzo

doi:10.1016/j.redox.2022.102268

Cited by 25 publications

(20 citation statements)

References 60 publications

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“…PDX stabilized from primary pediatric T-ALL samples were propagated in NOD/SCID mice. The xenograft cells were recovered from the spleens of mice that developed leukemia and used in in vitro assays as previously described [ 7 , 11 , 12 ]. Primary samples from T-ALL patients were obtained in compliance with the Code of Ethics of the World Medical Association Declaration of Helsinki in the context of the AIEOP BFM ALL 2009 protocol.…”

Section: Methodsmentioning

confidence: 99%

“…T-ALL cells are characterized by a rewiring of the homeostatic set point of reactive oxygen species (ROS) [ 3 , 4 ], which increases the vulnerability of these cells to ROS-inducing stimuli [ 5 , 6 ]. We previously showed that pharmacological inhibition of mTORC1 using everolimus or genetic silencing of components of this pathway results in a sustained elevation of ROS levels and primes T-ALL cells to apoptosis [ 7 ]. Interestingly, mTOR inhibition resulted in a decrease in the levels of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP), which is a principal source of cytosolic NADPH, an electron donor needed to maintain ROS scavengers in their reduced/active state.…”

Section: Introductionmentioning

confidence: 99%

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Repurposing Verapamil to Enhance Killing of T-ALL Cells by the mTOR Inhibitor Everolimus

et al. 2023

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New therapies are needed for patients with T-cell lymphoblastic leukemia (T-ALL) who do not respond to standard chemotherapy. Our previous studies showed that the mTORC1 inhibitor everolimus increases reactive oxygen species (ROS) levels, decreases the levels of NADPH and glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP), and induces apoptosis in T-ALL cells. Studies in T-ALL-xenografted NOD/SCID mice demonstrated that everolimus improved their response to the glucocorticoid (GC) dexamethasone. Here we show that verapamil, a calcium antagonist used in the treatment of supraventricular tachyarrhythmias, enhanced the effects of everolimus on ROS and cell death in T-ALL cell lines. The death-enhancing effect was synergistic and was confirmed in assays on a panel of therapy-resistant patient-derived xenografts (PDX) and primary samples from T-ALL patients. The verapamil-everolimus combination produced a dramatic reduction in the levels of G6PD and induction of p38 MAPK phosphorylation. Studies of NOD/SCID mice inoculated with refractory T-ALL PDX cells demonstrated that the addition of verapamil to everolimus plus dexamethasone significantly reduced tumor growth in vivo. Taken together, our results provide a rationale for repurposing verapamil in association with mTORC inhibitors and GC to treat refractory T-ALL.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Repurposing Verapamil to Enhance Killing of T-ALL Cells by the mTOR Inhibitor Everolimus

et al. 2023

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“…Everolimus is one of the earliest first-generation rapalog mTORC1 inhibitor approved by the United States FDA for advanced/metastatic renal cell carcinoma [32,33] . Everolimus treatment showed moderate pS6 reduction (27 %) in Jurkat cells as it is shown to specifically affect mTORC1 dependent pS6 rather than Akt [34][35][36] . Similarly, cell cycle arrest of Jurkat cells in G1 phase can be explained by PI3K/Akt/mTOR/p70 ribosomal S6 Kinase 1 (p70S6K1) inhibition as previously shown in breast cancer cell line i.e.…”

Section: Lncrna Expression Levels Differed Between Dual Andmentioning

confidence: 97%

Dual Inhibition of PI3K/Akt/mTOR Signaling Pathway in Leukemic Cell Lines Upregulates Long Non-Coding RNAs RNCR3 UCA1 and HULC

Aljuhani¹,

Almogbel²,

Khan³

et al. 2022

IJPS

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Decades of comprehensive research have resulted in a better understanding of the crucial role of phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin signaling in different types of leukemia whereby it strongly influences the growth and survival of cancerous cells. Recently, small-molecule inhibitors have been introduced as targeted therapies that are more tolerable than conventional antineoplastic drugs for leukemia. The growth inhibition assays were performed to assess the effectiveness of phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin pathway inhibitors like everolimus, torkinib and phosphokinase inhibitor 402 in leukemia cell lines. The cell cycle profiles, protein kinase B and S6 phosphorylations were assessed by flow cytometry. We also screened the expression of 96 cancer-associated long non-coding RNAs upon phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin pathway inhibition. Compared to untreated cells, the smallmolecule inhibitors treated cells showed reduced viability. Phosphokinase inhibitor 402, a dual pathway inhibitor was most effective in all cell lines (56.6 %, 32.5 % and 11.4 % in Jurkat, HL-60 and K562 cells, respectively). In addition, treatment with this resulted to shift the cells to the G1 phase from the S1 phase (Jurkat, G1: 12.2 %, S1: 4.9 %; HL-60, G1: 38.4 %, S1: 44.4 %; K562 G1: 14.4 %, S1: 15.7 %), more effectively than everolimus or torkinib. It was observed that when this inhibitor was used, the long non-coding RNAs retinal non-coding RNA 3 (3-fold) and highly up-regulated in liver cancer (2-fold) levels were significantly elevated whereas antisense non-coding ribonucleic acid in the INK4 locus and zinc finger homeobox 2 were significantly decreased by at least 25 %. Our findings revealed that dualspecificity inhibitors are more potent than single-specificity inhibitors. Hence, dual-targeted therapy may be a promising therapeutic option for leukemia. In addition, long non-coding RNAs may play a key role in drug resistance and could be a potential novel therapeutic target.

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“…mTOR stimulation is a common finding of T-ALL. Silic-Benussi et al evaluated the correlation between the mTOR pathway and redox equilibrium employing inhibitors and gene silencing [ 131 ]. In vitro experiments performed on T-ALL cells and steroid-resistant patient-originated T-ALL xenograft cells showed that the mTOR inhibitor everolimus augmented ROS concentrations, increased lipid peroxidation, and stimulated the ROS-regulated transcription factor NRF2.…”

Section: Oxidative Stress and Acute Lymphoblastic Leukemiamentioning

confidence: 99%

Targeting Redox Regulation as a Therapeutic Opportunity against Acute Leukemia: Pro-Oxidant Strategy or Antioxidant Approach?

et al. 2022

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Redox adaptation is essential for human health, as the physiological quantities of non-radical reactive oxygen species operate as the main second messengers to regulate normal redox reactions by controlling several sensors. An abnormal increase reactive oxygen species, called oxidative stress, induces biological injury. For this reason, variations in oxidative stress continue to receive consideration as a possible approach to treat leukemic diseases. However, the intricacy of redox reactions and their effects might be a relevant obstacle; consequently, and alongside approaches aimed at increasing oxidative stress in neoplastic cells, antioxidant strategies have also been suggested for the same purpose. The present review focuses on the molecular processes of anomalous oxidative stress in acute myeloid and acute lymphoblastic leukemias as well as on the oxidative stress-determined pathways implicated in leukemogenic development. Furthermore, we review the effect of chemotherapies on oxidative stress and the possibility that their pharmacological effects might be increased by modifying the intracellular redox equilibrium through a pro-oxidant approach or an antioxidant strategy. Finally, we evaluated the prospect of varying oxidative stress as an efficacious modality to destroy chemoresistant cells using new methodologies. Altering redox conditions may be advantageous for inhibiting genomic variability and the eradication of leukemic clones will promote the treatment of leukemic disease.

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mTOR inhibition downregulates glucose-6-phosphate dehydrogenase and induces ROS-dependent death in T-cell acute lymphoblastic leukemia cells

Cited by 25 publications

References 60 publications

Repurposing Verapamil to Enhance Killing of T-ALL Cells by the mTOR Inhibitor Everolimus

Repurposing Verapamil to Enhance Killing of T-ALL Cells by the mTOR Inhibitor Everolimus

Dual Inhibition of PI3K/Akt/mTOR Signaling Pathway in Leukemic Cell Lines Upregulates Long Non-Coding RNAs RNCR3 UCA1 and HULC

Targeting Redox Regulation as a Therapeutic Opportunity against Acute Leukemia: Pro-Oxidant Strategy or Antioxidant Approach?

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