Valproic acid disables the Nrf2 anti-oxidant response in acute myeloid leukaemia cells enhancing reactive oxygen species-mediated killing.
Authors
Jiang, Yao
Southam, Andrew D
Trova, Sandro
Beke, Flavio
Alhazmi, Bader
Francis, Thomas
Radotra, Anshul
di Maio, Alessandro
Drayson, Mark T
Bunce, Chris M
Publication Date
2022-02Journal Title
Br J Cancer
ISSN
0007-0920
Publisher
Springer Science and Business Media LLC
Volume
126
Issue
2
Pages
275-286
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Jiang, Y., Southam, A. D., Trova, S., Beke, F., Alhazmi, B., Francis, T., Radotra, A., et al. (2022). Valproic acid disables the Nrf2 anti-oxidant response in acute myeloid leukaemia cells enhancing reactive oxygen species-mediated killing.. Br J Cancer, 126 (2), 275-286. https://doi.org/10.1038/s41416-021-01570-z
Abstract
BACKGROUND: We previously demonstrated the in vitro killing of AML cells by the combination of the lipid-lowering agent bezafibrate (BEZ) and the contraceptive hormone medroxyprogesterone acetate (MPA). A phase II trial demonstrated in vivo safety and efficacy of BEZ and MPA (BaP) in elderly, relapsed/refractory AML and high-risk myelodysplastic syndrome (MDS) patients. However, we observed dose-limiting toxicities in a second trial that attempted to improve outcomes via escalation of BaP doses. Thus we sought to identify a third repurposed drug that potentiates activity of low dose BaP (BaP 0.1 mM). METHODS AND RESULTS: We demonstrate that addition of a commonly used anti-epileptic, valproic acid (VAL) to low dose BaP (BaP 0.1 mM)(VBaP) enhanced killing of AML cell lines/primary AML cells to levels similar to high dose BaP (BaP 0.5 mM). Similarly, addition of VAL to BaP 0.1 mM enhanced reactive oxygen species (ROS), lipid peroxidation and inhibition of de novo fatty acid synthesis. Overexpression of Nrf2 in K562 and KG1a completely inhibited ROS production and rescued cells from VAL/BaP 0.1 mM/VBaP killing. CONCLUSIONS: Given the good safety data of low-dose BaP in elderly/relapsed/refractory AML patients, and that VAL alone is well-tolerated, we propose VBaP as a novel therapeutic combination for AML.
Keywords
Article, /631/67/1990/283, /692/308/153, article
Sponsorship
Bloodwise (13028, 13028)
Identifiers
s41416-021-01570-z, 1570
External DOI: https://doi.org/10.1038/s41416-021-01570-z
This record's URL: https://www.repository.cam.ac.uk/handle/1810/333171
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
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