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

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.

The Role of E3 ubiquitin Ligase WWP2 and the Regulation of PARP1 by Ubiquitinated Degradation in Apoptosis of Acute Lymphoblastic Leukemia

“…Proteins such as membrane proteins, cell cycle regulators, transcription factors, tumor suppressors and oncogenes, are ubiquitinated and play roles in different cellular activities (4,5,7). Ubiquitin-proteasome pathway is reported to be essential in leukemia (30)(31)(32) and ubiquitin ligases participated in the development and resistance of different leukemia (33)(34)(35)(36). Therefore, we had a thought that WWP2 play roles in apoptosis of ALL by regulate substrate protein as ubiquitin ligase by ubiquitin-proteasome pathway.…”

The role of E3 ubiquitin ligase WWP2 and the regulation of PARP1 by ubiquitinated degradation in acute lymphoblastic leukemia

“…Proteins such as membrane proteins, cell cycle regulators, transcription factors, tumor suppressors and oncogenes, are ubiquitinated and play roles in different cellular activities [4,5,7]. Ubiquitin-proteasome pathway is reported to be essential in leukemia [28][29][30] and ubiquitin ligases participated in the development and resistance of different leukemia [31][32][33][34]. And it was reported that E3 ubiquitin ligases also play other roles in leukemia.…”

Bioactive Molecules: Structures, Functions, and Potential Uses for Cancer Prevention and Targeted Therapies

“…The induction of oxidative stress, depletion of glutathione, and induction of high-molecular-weight (HMW) complexes by these compounds have also been reported. Selvaraju and colleagues [ 3 ] reported that sensitivity of acute myelocytic leukemia (AML) cells to the dienone compound VLX1570 is associated with UPS inhibition. The authors first examined the response of AML cells to VLX1570.…”