The activity of therapeutic molecular cluster Ag5 is dependent on oxygen level and HIF-1 mediated signalling.

Autor:	Twigger SA; Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK., Dominguez B; Department of physiology and CIMUS Universidade de Santiago de Compostela, Spain., Porto V; Department of physiology and CIMUS Universidade de Santiago de Compostela, Spain., Hacker L; Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK., Chalmers AJ; School of Cancer Sciences, University of Glasgow, UK., Breckenridge R; Arjuna Therapeutics, Milladoiro, Spain., Treder M; Arjuna Therapeutics, Milladoiro, Spain., Sedgwick AC; Department of Chemistry, King's College London, London, SE1 1DB, UK., Dominguez F; Department of physiology and CIMUS Universidade de Santiago de Compostela, Spain., Hammond EM; Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK. Electronic address: ester.hammond@oncology.ox.ac.uk.
Jazyk:	angličtina
Zdroj:	Redox biology [Redox Biol] 2024 Oct; Vol. 76, pp. 103326. Date of Electronic Publication: 2024 Aug 22.
DOI:	10.1016/j.redox.2024.103326
Abstrakt:	Regions of hypoxia occur in most solid tumours and are known to significantly impact therapy response and patient prognosis. Ag5 is a recently reported silver molecular cluster which inhibits both glutathione and thioredoxin signalling therefore limiting cellular antioxidant capacity. Ag5 treatment significantly reduces cell viability in a range of cancer cell lines with little to no impact on non-transformed cells. Characterisation of redox homeostasis in hypoxia demonstrated an increase in reactive oxygen species and glutathione albeit with different kinetics. Significant Ag5-mediated loss of viability was observed in a range of hypoxic conditions which mimic the tumour microenvironment however, this effect was reduced compared to normoxic conditions. Reduced sensitivity to Ag5 in hypoxia was attributed to HIF-1 mediated signalling to reduce PDH via PDK1/3 activity and changes in mitochondrial oxygen availability. Importantly, the addition of Ag5 significantly increased radiation-induced cell death in hypoxic conditions associated with radioresistance. Together, these data demonstrate Ag5 is a potent and cancer specific agent which could be used effectively in combination with radiotherapy. Competing Interests: Declaration of competing interest RB is the CEO and Board Director of Arjuna Therapeutics. MT is the CSO of Arjuna Therapeutics. FD is scientific advisor and shareholder of Arjuna Therapeutics and has patents on Ag5 synthesis and the therapeutic applications. (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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