A novel Gboxin analog induces OXPHOS inhibition and mitochondrial dysfunction-mediated apoptosis in diffuse large B-cell lymphoma

Yao, Si; Yin, Jie; Li, Wen; Li, Yang; Huang, Jian-Zheng; Qi, Changxing; Hu, Zhengxi; Tong, Qingyi; Gu, Lianghu; Zhang, Yonghui

doi:10.1016/j.bioorg.2022.106019

Cited by 3 publications

(3 citation statements)

References 44 publications

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“…As an OxPhos inhibitor, the Gboxin analog 5d has specific selectivity for DLBCL. Given its strong proliferation inhibition and cell cycle-blocking effects on DLBCL, 5d is considered a candidate agent for DLBCL alternative drug development ( 34 ). In conclusion, the TCA cycle and mitochondrial oxidative respiration are closely associated with DLBCL.…”

Section: Discussionmentioning

confidence: 99%

“…They hypothesized that tumor cells meet their own TCA cycle substrate requirements by mediating stromal cell metabolic reorganization ( 33 ). Not surprisingly, the oxidative phosphorylation inhibitor Gboxin analog was found to have a strong proliferation inhibitory and cell cycle blocking effect on DLBCL with specific selectivity for it ( 34 ). Several recent studies have revealed the potential role of CRGs in the prognosis of cancers, such as kidney cancer ( 35 – 42 ), hepatocellular carcinoma ( 43 – 47 ), lung cancer ( 48 – 53 ), head and neck squamous cell carcinoma ( 53 – 60 ), glioma ( 61 – 66 ), breast cancer ( 67 – 70 ), endometrial carcinoma ( 71 , 72 ), melanoma ( 73 – 75 ), pancreatic cancer ( 76 , 77 ), colorectal cancer ( 78 – 81 ) and so on.…”

Section: Introductionmentioning

confidence: 99%

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Development and validation of a cuproptosis-associated prognostic model for diffuse large B-cell lymphoma

Zhang

Zhang²,

Zheng³

et al. 2023

Front. Oncol.

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Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous disease. Therefore, more reliable biomarkers are required to better predict the prognosis of DLBCL. Cuproptosis is a novel identified form of programmed cell death (PCD) that is different from oxidative stress-related cell death (e.g., apoptosis, ferroptosis, and necroptosis) by Tsvetkov and colleagues in a recent study released in Science. Cuproptosis is copper-dependent PCD that is closely tied to mitochondrial metabolism. However, the prognostic value of cuproptosis-related genes (CRGs) in DLBCL remains to be further elucidated. In the present study, we systematically evaluated the molecular changes of CRGs in DLBCL and found them to be associated with prognosis. Subsequently, based on the expression profiles of CRGs, we characterized the heterogeneity of DLBCL by identifying two distinct subtypes using consensus clustering. Two isoforms exhibited different survival, biological functions, chemotherapeutic drug sensitivity, and immune microenvironment. After identifying differentially expressed genes (DEGs) between CRG clusters, we built a prognostic model with the Least absolute shrinkage and selection operator (LASSO) Cox regression analysis and validated its prognostic value by Cox regression analysis, Kaplan-Meier curves, and receiver operating characteristic (ROC) curves. In addition, the risk score can predict clinical characteristics, levels of immune cell infiltration, and prognosis. Furthermore, a nomogram incorporating clinical features and risk score was generated to optimize risk stratification and quantify risk assessment. Compared to the International Prognostic Index (IPI), the nomogram has demonstrated more accuracy in survival prediction. Furthermore, we validated the prognostic gene expression levels through external experiments. In conclusion, cuproptosis-related gene signature can serve as a potential prognostic predictor in DLBCL patients and may provide new insights into cancer therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Development and validation of a cuproptosis-associated prognostic model for diffuse large B-cell lymphoma

Zhang

Zhang²,

Zheng³

et al. 2023

Front. Oncol.

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“…[1] Currently, the main clinical treatment for mitochondrial permeability transition pore and relatively high mitochondrial proton gradient in GBM cells, Gboxin with positive charge could inhibit the oxidative phosphorylation (OX-PHOS) and ATP generation and thus achieve specific lethal to GBM cell death while sparing normal primary low-passage cells. Although the specific killing and low side-effect of Gboxin have inspired further research on the application of Gboxin and the analogs for cancer therapy, [9] there are two major concerns hindering the substantial clinical benefits. [10] On the one hand, Gboxin with poor metabolic stability and pharmacokinetic properties is hard to penetrate the BBB to achieve sufficient tumoral accumulation and infiltration for thorough eradication of GBM CSCs, asking for drug-delivery nanoplatforms for targeted therapy.…”

Section: Introductionmentioning

confidence: 99%

Simultaneous Modulation of Hypoxia And Metabolism in Glioblastoma for Enhanced Radio‐Immunotherapy

Xie,

Zhang,

Zhao

et al. 2023

Adv Funct Materials

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Glioblastoma (GBM) is the most invasive and lethal primary brain melanoma. The existing treatment modality is unable to achieve thorough elimination of GBM due to the aggressive nature, blood‐brain barrier (BBB), hypoxic environment, and heterogeneous cellular components. Herein, a radio‐immunotherapy regimen based on a versatile nanoplatform (G/APH‐M) is proposed to effectively kill quiescent cancer stem cells (CSCs) and proliferative cancer cells in GBM in a simultaneous manner. Among o ur prepared G/APH‐M, the coating of GL261 cell membrane guarantees the BBB‐penetrable delivery and homologous GBM‐targeting of the hollow Prussian blue loaded with oxidative phosphorylation inhibitor Gboxin and catalase‐mimetic nanozymes. After substantial tumor accumulation, the released Gboxin inhibits mitochondrial oxidative phosphorylation to kill CSCs, while the nanozymes catalyze the production of oxygen to enhance radiotherapy. Consequently, potent immunogenic cell death (ICD) of GBM is induced, which in combination with immune checkpoint inhibitors (αPD‐L1), achieving a potent therapeutic effect with an 80% survival rate in the orthotopic GBM model even at 60 days after the treatment. The synergistic modulation of hypoxia and metabolism based on G/APH‐M greatly intensifies the radio‐immunotherapy of GBM, which would inspire more comprehensive strategies targeting the multiple characteristics of GBM cells for clinical benefits.

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Y9, a Gboxin analog, displays anti-tumor effect in non-small cell lung cancer by inducing lysosomal dysfunction and apoptosis

Yin,

Ding,

Yao

et al. 2024

Bioorganic Chemistry

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A novel Gboxin analog induces OXPHOS inhibition and mitochondrial dysfunction-mediated apoptosis in diffuse large B-cell lymphoma

Cited by 3 publications

References 44 publications

Development and validation of a cuproptosis-associated prognostic model for diffuse large B-cell lymphoma

Development and validation of a cuproptosis-associated prognostic model for diffuse large B-cell lymphoma

Simultaneous Modulation of Hypoxia And Metabolism in Glioblastoma for Enhanced Radio‐Immunotherapy

Y9, a Gboxin analog, displays anti-tumor effect in non-small cell lung cancer by inducing lysosomal dysfunction and apoptosis

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