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

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

doi:10.1038/s41416-021-01570-z

Abstract

BackgroundWe 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 ResultsWe 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.ConclusionsGiven 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.

Highlights

Acute myeloid leukaemias (AML) are aggressive blood cancers that, if untreated, kill patients quickly by crippling production of normal blood cells
VBaP-induced AML cell death was associated with Annexin V (AV) positivity, a marker associated with apoptosis (Fig. 1b)
We have shown here that the addition of clinically achievable doses of Valproic acid (VAL) to low dose BEZ and MPA (BaP) 0.1 mM (VBaP) recapitulates the killing of primary AML cells and AML cell lines seen in response to BaP 0.5 mM

Summary

Introduction

Acute myeloid leukaemias (AML) are aggressive blood cancers that, if untreated, kill patients quickly by crippling production of normal blood cells. Treatment is focused on the high rate of cell division in AML cells but this focus kills the rapidly dividing progenitors of normal blood cells. Treatment is tempered into short cycles that allow recovery of normal blood cell production from haemopoietic stem cells (HSCs) between treatment cycles. AML is most prevalent in the elderly and >70% of patients are older than 60 years at diagnosis. Cannot tolerate these repeated cycles of intensive cytotoxic chemotherapy because of their age and disease related frailty [1, 2]. There is an urgent need to identify therapies that target cancer cell characteristics with no/limited toxicity to normal cells and ideally a good known clinical safety profile

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Conclusion