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Nitro-Deficient Niclosamide Confers Reduced Genotoxicity and Retains Mitochondrial Uncoupling Activity for Cancer Therapy
- Source :
- International Journal of Molecular Sciences, Volume 22, Issue 19, International Journal of Molecular Sciences, Vol 22, Iss 10420, p 10420 (2021)
- Publication Year :
- 2021
- Publisher :
- Multidisciplinary Digital Publishing Institute, 2021.
-
Abstract
- Niclosamide is an oral anthelmintic drug, approved for use against tapeworm infections. Recent studies suggest however that niclosamide may have broader clinical applications in cancers, spurring increased interest in the functions and mechanisms of niclosamide. Previously, we reported that niclosamide targets a metabolic vulnerability in p53-deficient tumours, providing a basis for patient stratification and personalised treatment strategies. In the present study, we functionally characterised the contribution of the aniline 4′-NO2 group on niclosamide to its cellular activities. We demonstrated that niclosamide induces genome-wide DNA damage that is mechanistically uncoupled from its antitumour effects mediated through mitochondrial uncoupling. Elimination of the nitro group in ND-Nic analogue significantly reduced γH2AX signals and DNA breaks while preserving its antitumour mechanism mediated through a calcium signalling pathway and arachidonic acid metabolism. Lipidomics profiling further revealed that ND-Nic-treated cells retained a metabolite profile characteristic of niclosamide-treated cells. Notably, quantitative scoring of drug sensitivity suggests that elimination of its nitro group enhanced the target selectivity of niclosamide against p53 deficiency. Importantly, the results also raise concern that niclosamide may impose a pleiotropic genotoxic effect, which limits its clinical efficacy and warrants further investigation into alternative drug analogues that may ameliorate any potential unwanted side effects.
- Subjects :
- Drug
p53
QH301-705.5
DNA damage
media_common.quotation_subject
Metabolite
Pharmacology
medicine.disease_cause
Article
Catalysis
Inorganic Chemistry
chemistry.chemical_compound
Neoplasms
Lipidomics
medicine
Humans
Biology (General)
Physical and Theoretical Chemistry
QD1-999
Molecular Biology
Spectroscopy
Niclosamide
media_common
Calcium signaling
mitochondrial uncoupling
Chemistry
Organic Chemistry
niclosamide
genotoxicity
General Medicine
HCT116 Cells
Mitochondria
Computer Science Applications
Nitro
lipidomics
Genotoxicity
DNA Damage
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 14220067
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences
- Accession number :
- edsair.doi.dedup.....71d0c0d80aa696d530386119cf4994ff
- Full Text :
- https://doi.org/10.3390/ijms221910420