期刊
BIOMOLECULES
卷 11, 期 9, 页码 -出版社
MDPI
DOI: 10.3390/biom11091339
关键词
acute myeloid leukemia; proteasome; ubiquitin; deubiquitinase; zebrafish
资金
- Cancerfonden
- Vetenskapsradet
- Radiumhemmets forskningsfonder
- Mary Beves Stiftelse
- Knut and Alice Wallenbergs forskningsstiftelse
The dienone compound VLX1570 exhibits tumor cell selectivity, targeting the ubiquitin-proteasome system (UPS) in acute myeloid leukemia (AML) cells. It induces ER stress, accumulation of ubiquitin complexes, and loss of cell viability in a dose-dependent manner, with Caspase activation but not glutathione depletion correlating to sensitivity.
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.
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