Author: Ashoub, Muhammad Hossein ; Katoueezadeh, Maryam ; Maleki, Parisa ; Nurain, Ismaila Olanrewaju ; Valandani, Hajar Mardani ; Torabizadeh, Seyedeh Atekeh ; Farsinejad, Alireza ; Fatemi, Ahmad ; Khalilabadi, Roohollah Mirzaee

BACKGROUNDDue to the high demand for novel approaches for leukemia-targeted therapy, this study investigates the impact of DNA-PK inhibitor NU7441 on the sensitivity of pre-B ALL cells to the telomerase inhibitor MST-312.METHODSThe study involved NALM-6 cells treated with MST-312 and NU7441, assessing their viability and metabolic activity using trypan blue and MTT assays. The study also evaluated apoptosis, gene expression changes, and DNA damage using flow cytometry, qRT-PCR, and micronucleus assays. The binding energy of MST-312 in the active site of telomerase was calculated using molecular docking.RESULTSThe study's findings revealed a synergistic decline in both cell viability and metabolic activity in NALM-6 cells when exposed to the combined treatment of MST-312 and NU7441, and this decrease occurred without any adverse effects on healthy PBMC cells. Furthermore, the combination treatment exhibited a significantly higher induction of apoptosis than treatment with MST-312 alone, as observed through flow cytometry assay. qRT-PCR analysis revealed that this enhanced apoptosis was associated with a notable downregulation of Bcl-2 expression and an upregulation of Bax gene expression. Moreover, the combination therapy decreased expression levels of hTERT and c-Myc genes. The micronucleus assay indicated that the combination treatment increased DNA damage in NALM-6 cells. Also, a good conformation between MST-312 and the active site of telomerase was revealed by docking data.CONCLUSIONSThe study suggests that simultaneous inhibition of telomerase and DNA-PK in pre-B ALL presents a novel targeted therapy approach.

01 Oct 2024·Acta Biomaterialia

A manganese-doped layered double hydroxide loaded with lactate oxidase and DNA repair inhibitors for synergistically enhanced tumor immunotherapy

Article

Author: Liu, Xihong ; Zhuo, Yuhong ; Cai, Kaiyong ; Li, Yan ; Chen, Peiran ; Yang, Bangliu ; Lu, Xiaotong ; Ren, Yu ; Zhang, Mingyue ; Qi, Chao ; Huang, Chengyao ; Zhang, Ke

Tumor immunotherapy has gained more and more attention in tumor treatment. However, the accumulation of lactic acid in tumor tissue inhibits the response of immune cells to form an immunosuppressive microenvironment (ISME). To reverse the ISME, an acid-responsive nanoplatform (termed as MLLN@HA) is reported for synergistically enhanced tumor immunotherapy. MLLN@HA is constructed by the co-loading of lactate oxidase (LOX) and DNA repair inhibitor (NU7441) in a manganese-doped layered double hydroxide (Mn-LDH), and then modified with hyaluronic acid (HA) for tumor-targeted delivery. After endocytosis by tumor cells, MLLN@HA decomposes and releases LOX, NU7441 and Mn²⁺ ions in the acidic tumor microenvironment. The released LOX catalyzes the conversion of lactic acid into hydrogen peroxide (H₂O₂), which not only alleviates the ISME, but also provides reactants for the Mn²⁺-mediated Fenton-like reaction to enhance chemodynamic therapy (CDT). Released NU7441 prevents CDT-induced DNA damage from being repaired, thereby increasing double-stranded DNA (dsDNA) fragments within tumor cells. Importantly, the released Mn²⁺ ions enhance the sensitivity of cyclic GMP-AMP synthase (cGAS) to dsDNA fragments, and activate the stimulator of interferon genes (STING) to induce an anti-tumor immune response. Such an orchestrated immune-boosting strategy ultimately achieves effective tumor growth inhibition and prevents tumor lung metastasis. STATEMENT OF SIGNIFICANCE: To improve the efficacy of tumor immunotherapy, an innovative acid-responsive MLLN@HA nanoplatform was developed for synergistically enhanced tumor immunotherapy. The MLLN@HA actively targets to tumor cells through the interaction of HA with CD44, and then degrades to release LOX, NU7441 and Mn²⁺ ions in the acidic tumor microenvironment. The released LOX generates H₂O₂ for the Mn²⁺-mediated Fenton reaction and reverses the ISME by consuming lactate. NU7441 prevents DNA damage repair, leading to an increased concentration of free DNA fragments, while Mn²⁺ ions activate the cGAS-STING pathway, enhancing the systemic anti-tumor immune response. The orchestrated immune-boosting nanoplatform effectively inhibits tumor growth and lung metastasis, presenting a promising strategy for cancer treatment.

05 Aug 2024·Neuro-Oncology

ARF4-mediated retrograde trafficking as a driver of chemoresistance in glioblastoma

Article

Author: McManus, Graysen ; Chen, Li ; Park, Cheol H ; Sonabend, Adam M ; James, C David ; Cho, Sia ; Heiland, Dieter H ; Perrault, Ella N ; Budhiraja, Shreya ; Dmello, Crismita ; Ahmed, Atique U ; Baisiwala, Shivani ; Kazi, Hasaan A ; Saathoff, Miranda ; Lin, Peiyu

AbstractBackgroundCellular functions hinge on the meticulous orchestration of protein transport, both spatially and temporally. Central to this process is retrograde trafficking, responsible for targeting proteins to the nucleus. Despite its link to many diseases, the implications of retrograde trafficking in glioblastoma (GBM) are still unclear.MethodsTo identify genetic drivers of TMZ resistance, we conducted comprehensive CRISPR-knockout screening, revealing ADP-ribosylation factor 4 (ARF4), a regulator of retrograde trafficking, as a major contributor.ResultsSuppressing ARF4 significantly enhanced TMZ sensitivity in GBM patient-derived xenograft (PDX) models, leading to improved survival rates (P < .01) in both primary and recurrent lines. We also observed that TMZ exposure stimulates ARF4-mediated retrograde trafficking. Proteomics analysis of GBM cells with varying levels of ARF4 unveiled the influence of this pathway on EGFR signaling, with increased nuclear trafficking of EGFR observed in cells with ARF4 overexpression and TMZ treatment. Additionally, spatially resolved RNA-sequencing of GBM patient tissues revealed substantial correlations between ARF4 and crucial nuclear EGFR (nEGFR) downstream targets, such as MYC, STAT1, and DNA-PK. Decreased activity of DNA-PK, a DNA repair protein downstream of nEGFR signaling that contributes to TMZ resistance, was observed in cells with suppressed ARF4 levels. Notably, treatment with DNA-PK inhibitor, KU-57788, in mice with a recurrent PDX line resulted in prolonged survival (P < .01), highlighting the promising therapeutic implications of targeting proteins reliant on ARF4-mediated retrograde trafficking.ConclusionsOur findings demonstrate that ARF4-mediated retrograde trafficking contributes to the development of TMZ resistance, cementing this pathway as a viable strategy to overcome chemoresistance in GBM.

100 Deals associated with NU7441

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	GB	The University of Newcastle	29 Oct 2005
Neoplasms	Preclinical	GB	KuDOS Pharmaceuticals Ltd.	29 Oct 2005

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