PLGA-nano-encapsulated disulfiram inhibits hypoxia-induced NF-κB, cancer stem cells, and targets glioblastoma in vitro and in vivo
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Kilari, Rajagopal Sharada
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AbstractGlioblastoma stem cell (GSC) is the major cause of glioblastoma multiforme (GBM) chemotherapy failure. Hypoxia is one of the determinants of GSC. NF-κB plays a pivotal link between hypoxia and cancer stem cells (CSCs). Disulfiram, an antialcoholism drug, has very strong NF-κB-inhibiting and anti-CSC activity. In this study, the in vitro anti-GSC activity of disulfiram and in vivo anti-GBM efficacy of poly lactic-co-glycolic acid nanoparticle-encapsulated disulfiram (DS-PLGA) were examined. We attempt to elucidate the molecular network between hypoxia and GSCs and also examined the anti-GSC activity of disulfiram in vitro and in vivo. The influence of GSCs and hypoxia on GBM chemoresistance and invasiveness was studied in hypoxic and spheroid cultures. The molecular regulatory roles of NF-κB, hypoxia-inducible factor-1α (HIF1α), and HIF2α were investigated using stably transfected U373MG cell lines. The hypoxia in neurospheres determines the cancer stem cell characteristics of the sphere-cultured GBM cell lines (U87MG, U251MG, U373MG). NF-κB is located at a higher hierarchical position than HIF1α/HIF2α in hypoxic regulatory network and plays a key role in hypoxia-induced GSC characters. DS inhibits NF-κB activity and targets hypoxia-induced GSCs. It showed selective toxicity to GBM cells, eradicates GSCs, and blocks migration and invasion at very low concentrations. DS-PLGA efficaciously inhibits orthotopic and subcutaneous U87MG xenograft in mouse models with no toxicity to vital organs.
CitationKannappan, V., Liu, Y., Wang, Z., Azar, K., Kurusamy, S., Kilari, R.S., Armesilla, A., Najlah, M., Liu, P., Bian, X. and Wang, W. (2022) PLGA-nano-encapsulated disulfiram inhibits hypoxia-induced NF-κB, cancer stem cells, and targets glioblastoma in vitro and in vivo. Molecular Cancer Therapeutics, 21(8), pp. 1273–1284.
PublisherAmerican Association for Cancer Research
JournalMolecular Cancer Therapeutics
PubMed ID35579893 (pubmed)
DescriptionThis is an accepted manuscript of an article published by the American Association for Cancer Research on 02/08/2022, available online: https://doi.org/10.1158/1535-7163.MCT-22-0066 The accepted version of the publication may differ from the final published version.
SponsorsThis study was supported by Research Institute in Healthcare Science/University of Wolverhampton PhD studentship; Innovate UK Jiangsu-UK Industrial Challenge Programme (104022); Some key equipment was jointly funded by European Regional Developmental Fund, Smart Concept Fund, University of Wolverhampton and Disulfican Ltd.
Except where otherwise noted, this item's license is described as https://creativecommons.org/licenses/by-nc-nd/4.0/
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