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PLGA-nano-encapsulated disulfiram inhibits hypoxia-induced NF-κB, cancer stem cells, and targets glioblastoma in vitro and in vivo
Kannappan, Vinodh Liu, Ying Wang, Zhipeng Azar, Karim Kurusamy, Sathishkumar Kilari, Rajagopal Sharada Najlah, Mohammad Liu, Peng Bian, Xiu-Wu
Kannappan, Vinodh
Liu, Ying
Wang, Zhipeng
Azar, Karim
Kurusamy, Sathishkumar
Kilari, Rajagopal Sharada
Najlah, Mohammad
Liu, Peng
Bian, Xiu-Wu
Editors
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Epub Date
Issue Date
2022-08-02
Submitted date
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Abstract
Glioblastoma 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.
Citation
Kannappan, 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.
Publisher
Journal
Research Unit
PubMed ID
35579893 (pubmed)
PubMed Central ID
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Type
Journal article
Language
en
Description
This 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.
Series/Report no.
ISSN
1535-7163
EISSN
1538-8514
ISBN
ISMN
Gov't Doc #
Sponsors
This 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.