Sensitivity of Acute Myelocytic Leukemia Cells to the Dienone Compound VLX1570 Is Associated with Inhibition of the Ubiquitin-Proteasome System.

Karthik Selvaraju,Maria Miquel,Pádraig D’Arcy,Lasse D Jensen,Amanda Nilsson,Stig Linder,Kourosh Lotfi,Johannes Gubat,Julia Hill

doi:10.3390/biom11091339

Abstract

Dienone compounds with a 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore have been widely reported to show tumor cell selectivity. These compounds target the ubiquitin-proteasome system (UPS), known to be essential for the viability of tumor cells. The induction of oxidative stress, depletion of glutathione, and induction of high-molecular-weight (HMW) complexes have also been reported. We here examined the response of acute myeloid leukemia (AML) cells to the dienone compound VLX1570. AML cells have relatively high protein turnover rates and have also been reported to be sensitive to depletion of reduced glutathione. We found AML cells of diverse cytogenetic backgrounds to be sensitive to VLX1570, with drug exposure resulting in an accumulation of ubiquitin complexes, induction of ER stress, and the loss of cell viability in a dose-dependent manner. Caspase activation was observed but was not required for the loss of cell viability. Glutathione depletion was also observed but did not correlate to VLX1570 sensitivity. Formation of HMW complexes occurred at higher concentrations of VLX1570 than those required for the loss of cell viability and was not enhanced by glutathione depletion. To study the effect of VLX1570 we developed a zebrafish PDX model of AML and confirmed antigrowth activity in vivo. Our results show that VLX1570 induces UPS inhibition in AML cells and encourage further work in developing compounds useful for cancer therapeutics.

Highlights

IntroductionThe presence of α,β-unsaturated ketones that function as Michael acceptors raises the possibility of general cysteine reactivity, many compounds of this class have been documented as tumor selective [1,2,3]
Compounds with a 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore (Figure 1) have attracted considerable interest as anticancer agents [1]. the presence of α,β-unsaturated ketones that function as Michael acceptors raises the possibility of general cysteine reactivity, many compounds of this class have been documented as tumor selective [1,2,3]
Dienone compounds with the 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore (Figure 1)

Summary

Introduction

The presence of α,β-unsaturated ketones that function as Michael acceptors raises the possibility of general cysteine reactivity, many compounds of this class have been documented as tumor selective [1,2,3]. A number of groups have shown that dienone compounds affect the ubiquitin-proteasome system (UPS) [2,4,5,6]. Malignant cells are sensitive to disturbances in the UPS primarily due to increased levels of protein production and a dependency on UPS-mediated degradation for the maintenance of homeostasis [7]. Several classes of dienone compounds have been shown to induce redox stress, either directly by inhibiting scavenging pathways or via the acute induction of reactive oxygen species (ROS) due to defective protein folding and degradation.

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Results

Conclusion