Valproic acid disables the Nrf2 anti-oxidant response in acute myeloid leukaemia cells enhancing reactive oxygen species-mediated killing

Yao Jiang, Andrew D. Southam, Sandro Trova, Flavio Beke, Bader Alhazmi, Thomas Francis, Anshul Radotra, Alessandro Di Maio, Mark T. Drayson, Chris M. Bunce, Farhat L. Khanim

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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.
Original languageEnglish
Pages (from-to)275-286
Number of pages7
JournalBritish Journal of Cancer
Volume126
Issue number2
DOIs
Publication statusPublished - 22 Oct 2021

Bibliographical note

Funding Information:
This study was funded by a Programme Grant (13028) from Blood Cancer UK awarded to FLK, MTD and CMB.

Publisher Copyright:
© 2021, The Author(s).

Publication date on PubMed is February 2022.

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