PUBLICATION
Sensitivity of Acute Myelocytic Leukemia Cells to the Dienone Compound VLX1570 Is Associated with Inhibition of the Ubiquitin-Proteasome System
- Authors
- Selvaraju, K., Lotfi, K., Gubat, J., Miquel, M., Nilsson, A., Hill, J., Jensen, L.D., Linder, S., D'Arcy, P.
- ID
- ZDB-PUB-210929-10
- Date
- 2021
- Source
- Biomolecules 11(9): (Journal)
- Registered Authors
- Keywords
- acute myeloid leukemia, deubiquitinase, proteasome, ubiquitin, zebrafish
- MeSH Terms
-
- Animals
- Azepines/chemistry
- Azepines/pharmacology*
- Benzylidene Compounds/chemistry
- Benzylidene Compounds/pharmacology*
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Cell Survival/drug effects
- Curcumin/pharmacology
- Embryo, Nonmammalian/drug effects
- Embryo, Nonmammalian/metabolism
- Endoplasmic Reticulum Stress/drug effects
- Glutathione/metabolism
- Heme Oxygenase-1/metabolism
- Humans
- Leukemia, Myeloid, Acute/pathology*
- Molecular Weight
- Polyubiquitin/metabolism
- Proteasome Endopeptidase Complex/metabolism*
- Time Factors
- Ubiquitin/antagonists & inhibitors*
- Ubiquitin/metabolism
- Ubiquitination/drug effects
- Zebrafish/embryology
- PubMed
- 34572552 Full text @ Biomolecules
Citation
Selvaraju, K., Lotfi, K., Gubat, J., Miquel, M., Nilsson, A., Hill, J., Jensen, L.D., Linder, S., D'Arcy, P. (2021) Sensitivity of Acute Myelocytic Leukemia Cells to the Dienone Compound VLX1570 Is Associated with Inhibition of the Ubiquitin-Proteasome System. Biomolecules. 11(9):.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping