Molecular Iodine/Cyclophosphamide Synergism on Chemoresistant Neuroblastoma Models

Álvarez-León, Winniberg; Mendieta, Irasema; Delgado‐González, Evangelina; Anguiano, Brenda; Aceves, Carmen

doi:10.3390/ijms22168936

Cited by 10 publications

(4 citation statements)

References 37 publications

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“…391 It is a prodrug, forming amino[bis(2chloroethyl)amino]phosphinic acid, which is an active antineoplastic ingredient, and acrolein (prop-2-enal), which is associated with side effects. Clinical studies have been initiated with other substances, such as iodine, 392 and drugs for advanced or metastatic breast cancer patients and mature B-cell non-Hodgkin lymphoma in children carrying wt and mutant p53. A recent CT enrolled patients with solid tumors and relapsed AML for clinical treatment with atorvastatin to decrease the mutant p53 protein levels.…”

Section: Targeting P53 L1/s3 and Y220c Mutant To Restore Wt P53 Functionmentioning

confidence: 99%

Targeting Biomolecular Condensation and Protein Aggregation against Cancer

et al. 2023

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Biomolecular condensates, membrane-less entities arising from liquid–liquid phase separation, hold dichotomous roles in health and disease. Alongside their physiological functions, these condensates can transition to a solid phase, producing amyloid-like structures implicated in degenerative diseases and cancer. This review thoroughly examines the dual nature of biomolecular condensates, spotlighting their role in cancer, particularly concerning the p53 tumor suppressor. Given that over half of the malignant tumors possess mutations in the TP53 gene, this topic carries profound implications for future cancer treatment strategies. Notably, p53 not only misfolds but also forms biomolecular condensates and aggregates analogous to other protein-based amyloids, thus significantly influencing cancer progression through loss-of-function, negative dominance, and gain-of-function pathways. The exact molecular mechanisms underpinning the gain-of-function in mutant p53 remain elusive. However, cofactors like nucleic acids and glycosaminoglycans are known to be critical players in this intersection between diseases. Importantly, we reveal that molecules capable of inhibiting mutant p53 aggregation can curtail tumor proliferation and migration. Hence, targeting phase transitions to solid-like amorphous and amyloid-like states of mutant p53 offers a promising direction for innovative cancer diagnostics and therapeutics.

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Section: Targeting P53 L1/s3 and Y220c Mutant To Restore Wt P53 Functionmentioning

confidence: 99%

Targeting Biomolecular Condensation and Protein Aggregation against Cancer

et al. 2023

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“…To explore the role of TAF1D in tumors, we established subcutaneous xenografts in BALB/c‐nude mice using SK‐N‐BE(2) cells infected with TAF1D ‐targeting or control shRNA as previously described 28 . TAF1D knockdown with either validated shRNA resulted in significantly smaller tumors compared with controls (Figure 5A–E).…”

Section: Resultsmentioning

confidence: 99%

“…To explore the role of TAF1D in tumors, we established subcutaneous xenografts in BALB/c-nude mice using SK-N-BE(2) cells infected with TAF1D-targeting or control shRNA as previously described. 28 TAF1D knockdown with either validated shRNA resulted in significantly smaller tumors compared with controls (Figure 5A-E). In agreement with our in vitro data, immunohistochemical staining showed that the proliferation marker, Ki-67, 29 was significantly lower in tumors from both TAF1D-knockdown groups compared with the control (Figure 5F).…”

Section: Taf1d Knockdown Limits the Growth Of Mycn-amplified Nb Tumorsmentioning

confidence: 96%

TAF1D promotes proliferation by transcriptionally activating G2/M phase‐related genes in MYCN‐amplified neuroblastoma

et al. 2023

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High‐risk neuroblastoma (HR‐NB) is an aggressive childhood cancer that responds poorly to currently available therapies and is associated with only about a 50% 5‐year survival rate. MYCN amplification is a critical driver of these aggressive tumors, but so far there have not been any approved treatments to effectively treat HR‐NB by targeting MYCN or its downstream effectors. Thus, the identification of novel molecular targets and therapeutic strategies to treat children diagnosed with HR‐NB represents an urgent unmet medical need. Here, we conducted a targeted siRNA screening and identified TATA box‐binding protein‐associated factor RNA polymerase I subunit D, TAF1D, as a critical regulator of the cell cycle and proliferation in HR‐NB cells. Analysis of three independent primary NB cohorts determined that high TAF1D expression correlated with MYCN‐amplified, high‐risk disease and poor clinical outcomes. TAF1D knockdown more robustly inhibited cell proliferation in MYCN‐amplified NB cells compared with MYCN‐non‐amplified NB cells, as well as suppressed colony formation and inhibited tumor growth in a xenograft mouse model of MYCN‐amplified NB. RNA‐seq analysis revealed that TAF1D knockdown downregulates the expression of genes associated with the G2/M transition, including the master cell‐cycle regulator, cell‐cycle‐dependent kinase 1 (CDK1), resulting in cell‐cycle arrest at G2/M. Our findings demonstrate that TAF1D is a key oncogenic regulator of MYCN‐amplified HR‐NB and suggest that therapeutic targeting of TAF1D may be a viable strategy to treat HR‐NB patients by blocking cell‐cycle progression and the proliferation of tumor cells.

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“…Most children with intermediate-risk and high-risk neuroblastoma will need to have chemotherapy and cyclophosphamide is one of the commonly used drugs [21][22][23][24]. We intend to explore whether the environment influences the tumor cell characteristics and the subsequent drug sensitivity after long time growth in orthotopic and subcutaneous mice, therefore, we reinoculated the tumor cells to different sites such as Ortho to Subq and Subq to Ortho.…”

Section: Discussionmentioning

confidence: 99%

Different tumorigenicity and distinct metastasis and gene signature between orthotopic and subcutaneous neuroblastoma xenografted mice

Han

Zhao

et al. 2022

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Patient-derived (PDX) and cell-derived (CDX) xenograft models are widely used in preclinical studies of human neuroblastoma. In this study, we constructed orthotopic and subcutaneous neuroblastoma CDX models by injecting human neuroblastoma cells into the adrenal gland and the flanks of immunodeficient mice, respectively. The tumorigenesis, metastasis and response to chemotherapy for the two models were also compared. Our results indicated that orthotopic tumor mice showed significantly faster tumor growth than that of subcutaneous mice. Importantly, the expression of PHOX2B and GAB2 was dramatically increased in the tumors of orthotopic CDX mice. Furthermore, orthotopic CDX mice developed multiple organ metastasis resembling that of neuroblastoma patients, while metastasis occurred predominantly in lung in subcutaneous CDX mice. Moreover, the two CDX models showed comparable response to cyclophosphamide treatment. Our results suggest that orthotopic CDX mice are superior to subcutaneous CDX mice as a preclinical model to study human neuroblastoma.

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Molecular Iodine/Cyclophosphamide Synergism on Chemoresistant Neuroblastoma Models

Cited by 10 publications

References 37 publications

Targeting Biomolecular Condensation and Protein Aggregation against Cancer

Targeting Biomolecular Condensation and Protein Aggregation against Cancer

TAF1D promotes proliferation by transcriptionally activating G2/M phase‐related genes in MYCN‐amplified neuroblastoma

Different tumorigenicity and distinct metastasis and gene signature between orthotopic and subcutaneous neuroblastoma xenografted mice

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