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A Novel Isotope-labeled Small Molecule Probe CC12 for Anti-glioma via Suppressing LYN-mediated Progression and Activating Apoptosis Pathways
Background: Glioblastoma multiforme (GBM) is the most lethal malignancy in brain, which is surrounded by the blood-brain barrier (BBB), which limits the efficacy of standard treatments. Developing an effective drug that can penetrate the blood-brain barrier (BBB) remains a critical challenge in the...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ivyspring International Publisher
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10321274/ https://www.ncbi.nlm.nih.gov/pubmed/37416766 http://dx.doi.org/10.7150/ijbs.82266 |
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author | Huang, Hsu-Shan Chiang, I-Tsang Lawal, Bashir Weng, Yueh-Shan Jeng, Long-Bin Kuo, Yu-Cheng Liu, Yu-Chang Hsu, Fei-Ting |
author_facet | Huang, Hsu-Shan Chiang, I-Tsang Lawal, Bashir Weng, Yueh-Shan Jeng, Long-Bin Kuo, Yu-Cheng Liu, Yu-Chang Hsu, Fei-Ting |
author_sort | Huang, Hsu-Shan |
collection | PubMed |
description | Background: Glioblastoma multiforme (GBM) is the most lethal malignancy in brain, which is surrounded by the blood-brain barrier (BBB), which limits the efficacy of standard treatments. Developing an effective drug that can penetrate the blood-brain barrier (BBB) remains a critical challenge in the fight against GBM. CC12 (NSC749232) is an anthraquinone tetraheterocyclic homolog with a lipophilic structure that may facilitate penetration of the brain area. Methods: We used temozolomide sensitive and resistance GBM cells and animal model to identify the CC12 delivery, anti-tumor potential and its underlying mechanism. Results: Importantly, toxicity triggered by CC12 was not associated with the methyl guanine-DNA methyl transferase (MGMT) methylation status which revealed a greater application potential compared to temozolomide. Alexa F488 cadaverine-labelled CC12 successfully infiltrated into the GBM sphere; in addition, (68)Ga-labeled CC12 was also found in the orthotopic GBM area. After passing BBB, CC12 initiated both caspase-dependent intrinsic/extrinsic apoptosis pathways and apoptosis-inducing factor, EndoG-related caspase-independent apoptosis signaling in GBM. RNA sequence analysis from The Cancer Genome Atlas indicated that LYN was overexpressed in GBM is associated with poorer overall survival. We proved that targeting of LYN by CC12 may diminish GBM progression and suppress it downstream factors such as signal transduction and activator of extracellular signal-regulated kinases (ERK)/transcription 3 (STAT3)/nuclear factor (NF)-κB. CC12 was also found to participate in suppressing GBM metastasis and dysregulation of the epithelial-mesenchymal transition (EMT) through inactivation of the LYN axis. Conclusion: CC12, a newly developed BBB-penetrating drug, was found to possess an anti-GBM capacity via initiating an apoptotic mechanism and disrupting LYN/ERK/STAT3/NF-κB-regulated GBM progression. |
format | Online Article Text |
id | pubmed-10321274 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
spelling | pubmed-103212742023-07-06 A Novel Isotope-labeled Small Molecule Probe CC12 for Anti-glioma via Suppressing LYN-mediated Progression and Activating Apoptosis Pathways Huang, Hsu-Shan Chiang, I-Tsang Lawal, Bashir Weng, Yueh-Shan Jeng, Long-Bin Kuo, Yu-Cheng Liu, Yu-Chang Hsu, Fei-Ting Int J Biol Sci Research Paper Background: Glioblastoma multiforme (GBM) is the most lethal malignancy in brain, which is surrounded by the blood-brain barrier (BBB), which limits the efficacy of standard treatments. Developing an effective drug that can penetrate the blood-brain barrier (BBB) remains a critical challenge in the fight against GBM. CC12 (NSC749232) is an anthraquinone tetraheterocyclic homolog with a lipophilic structure that may facilitate penetration of the brain area. Methods: We used temozolomide sensitive and resistance GBM cells and animal model to identify the CC12 delivery, anti-tumor potential and its underlying mechanism. Results: Importantly, toxicity triggered by CC12 was not associated with the methyl guanine-DNA methyl transferase (MGMT) methylation status which revealed a greater application potential compared to temozolomide. Alexa F488 cadaverine-labelled CC12 successfully infiltrated into the GBM sphere; in addition, (68)Ga-labeled CC12 was also found in the orthotopic GBM area. After passing BBB, CC12 initiated both caspase-dependent intrinsic/extrinsic apoptosis pathways and apoptosis-inducing factor, EndoG-related caspase-independent apoptosis signaling in GBM. RNA sequence analysis from The Cancer Genome Atlas indicated that LYN was overexpressed in GBM is associated with poorer overall survival. We proved that targeting of LYN by CC12 may diminish GBM progression and suppress it downstream factors such as signal transduction and activator of extracellular signal-regulated kinases (ERK)/transcription 3 (STAT3)/nuclear factor (NF)-κB. CC12 was also found to participate in suppressing GBM metastasis and dysregulation of the epithelial-mesenchymal transition (EMT) through inactivation of the LYN axis. Conclusion: CC12, a newly developed BBB-penetrating drug, was found to possess an anti-GBM capacity via initiating an apoptotic mechanism and disrupting LYN/ERK/STAT3/NF-κB-regulated GBM progression. Ivyspring International Publisher 2023-06-19 /pmc/articles/PMC10321274/ /pubmed/37416766 http://dx.doi.org/10.7150/ijbs.82266 Text en © The author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. |
spellingShingle | Research Paper Huang, Hsu-Shan Chiang, I-Tsang Lawal, Bashir Weng, Yueh-Shan Jeng, Long-Bin Kuo, Yu-Cheng Liu, Yu-Chang Hsu, Fei-Ting A Novel Isotope-labeled Small Molecule Probe CC12 for Anti-glioma via Suppressing LYN-mediated Progression and Activating Apoptosis Pathways |
title | A Novel Isotope-labeled Small Molecule Probe CC12 for Anti-glioma via Suppressing LYN-mediated Progression and Activating Apoptosis Pathways |
title_full | A Novel Isotope-labeled Small Molecule Probe CC12 for Anti-glioma via Suppressing LYN-mediated Progression and Activating Apoptosis Pathways |
title_fullStr | A Novel Isotope-labeled Small Molecule Probe CC12 for Anti-glioma via Suppressing LYN-mediated Progression and Activating Apoptosis Pathways |
title_full_unstemmed | A Novel Isotope-labeled Small Molecule Probe CC12 for Anti-glioma via Suppressing LYN-mediated Progression and Activating Apoptosis Pathways |
title_short | A Novel Isotope-labeled Small Molecule Probe CC12 for Anti-glioma via Suppressing LYN-mediated Progression and Activating Apoptosis Pathways |
title_sort | novel isotope-labeled small molecule probe cc12 for anti-glioma via suppressing lyn-mediated progression and activating apoptosis pathways |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10321274/ https://www.ncbi.nlm.nih.gov/pubmed/37416766 http://dx.doi.org/10.7150/ijbs.82266 |
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