Nitro-Deficient Niclosamide Confers Reduced Genotoxicity and Retains Mitochondrial Uncoupling Activity for Cancer Therapy

Ngai, Tsz Wai; Elfar, Gamal Ahmed; Yeo, Pearlyn; Phua, Nicholas; Hor, Jin Hui; Chen, Shuwen; Ho, Ying Swan; Cheok, Chit Fang

doi:10.3390/ijms221910420

Open AccessArticle

Nitro-Deficient Niclosamide Confers Reduced Genotoxicity and Retains Mitochondrial Uncoupling Activity for Cancer Therapy

by

Tsz Wai Ngai

^1,†,

Gamal Ahmed Elfar

^1,2,†,

Pearlyn Yeo

^1,2,

Nicholas Phua

¹,

Jin Hui Hor

¹,

Shuwen Chen

³

,

Ying Swan Ho

³ and

Chit Fang Cheok

^1,2,*

¹

Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138673, Singapore

²

Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore

³

Analytical Science and Technology (Metabolomics), Bioprocessing Technology Institute, 20 Biopolis Way, Centros #06-01, Singapore 138668, Singapore

^*

Author to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Int. J. Mol. Sci. 2021, 22(19), 10420; https://doi.org/10.3390/ijms221910420

Submission received: 16 July 2021 / Revised: 16 September 2021 / Accepted: 18 September 2021 / Published: 27 September 2021

(This article belongs to the Special Issue Mitochondrial Targeting as an Efficient Anti-cancer Therapy)

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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.

Keywords: niclosamide; genotoxicity; mitochondrial uncoupling; p53; lipidomics

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MDPI and ACS Style

Ngai, T.W.; Elfar, G.A.; Yeo, P.; Phua, N.; Hor, J.H.; Chen, S.; Ho, Y.S.; Cheok, C.F. Nitro-Deficient Niclosamide Confers Reduced Genotoxicity and Retains Mitochondrial Uncoupling Activity for Cancer Therapy. Int. J. Mol. Sci. 2021, 22, 10420. https://doi.org/10.3390/ijms221910420

AMA Style

Ngai TW, Elfar GA, Yeo P, Phua N, Hor JH, Chen S, Ho YS, Cheok CF. Nitro-Deficient Niclosamide Confers Reduced Genotoxicity and Retains Mitochondrial Uncoupling Activity for Cancer Therapy. International Journal of Molecular Sciences. 2021; 22(19):10420. https://doi.org/10.3390/ijms221910420

Chicago/Turabian Style

Ngai, Tsz Wai, Gamal Ahmed Elfar, Pearlyn Yeo, Nicholas Phua, Jin Hui Hor, Shuwen Chen, Ying Swan Ho, and Chit Fang Cheok. 2021. "Nitro-Deficient Niclosamide Confers Reduced Genotoxicity and Retains Mitochondrial Uncoupling Activity for Cancer Therapy" International Journal of Molecular Sciences 22, no. 19: 10420. https://doi.org/10.3390/ijms221910420

APA Style

Ngai, T. W., Elfar, G. A., Yeo, P., Phua, N., Hor, J. H., Chen, S., Ho, Y. S., & Cheok, C. F. (2021). Nitro-Deficient Niclosamide Confers Reduced Genotoxicity and Retains Mitochondrial Uncoupling Activity for Cancer Therapy. International Journal of Molecular Sciences, 22(19), 10420. https://doi.org/10.3390/ijms221910420

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Nitro-Deficient Niclosamide Confers Reduced Genotoxicity and Retains Mitochondrial Uncoupling Activity for Cancer Therapy

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