Sensitivity of Acute Myelocytic Leukemia Cells to the Dienone Compound VLX1570 Is Associated with Inhibition of the Ubiquitin-Proteasome System
Abstract
:1. Introduction
2. Materials and Methods
2.1. Cell Lines
2.2. Reagents and Antibodies
2.3. Cell Viability Assays
2.4. SDS PAGE and Immunoblotting
2.5. Glutathione Analysis
2.6. Developmental Toxicity Assay
2.7. Zebrafish Tumor Model
2.8. CMap Analysis
3. Results
3.1. Properties of Dienone Compounds
3.2. VLX1570 Induces the Loss of Viability of Acute Myelocytic Leukemia (AML) Cells
3.3. VLX1570 Induces Proteotoxic Stress and ER Stress in AML Cell Lines
3.4. VLX1570 Induces Glutathione Depletion and Formation of High-Molecular-Weight Protein Complexes
3.5. VLX1570 Inhibits Growth of AML Cells in Zebrafish Embryos
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Compound | Described Target(s) | Calculated Solubility a | PAINS b | LogP |
---|---|---|---|---|
b-AP15 | USP14/UCHL5 | −4.43 | yes | 2.08 |
VLX1570 | USP14/UCHL5 | −5.14 | yes | 2.91 |
RA-9 | USP14/UCHL5 | −3.95 | yes | 1.75 |
RA-190 | Rpn13/UCHL5 | −8.22 | yes | 5.49 |
F6 (NSC632839) | Deubiquitinases | −5.15 | yes | 3.60 |
EF24 | NFkB, MAPK, HIF-1α | −4.86 | yes | 3.62 |
Curcumin | Multiple targets | −3.94 | no | 3.03 |
NSC-632839 | Curcumin | |||
---|---|---|---|---|
Rank | Gene | Description | Gene | Description |
1 | PSMA1 | Proteasome subunit | TP53RK | Bud32 family |
2 | PSMD1 | Proteasome subunit | CD46 | CD molecules |
3 | PSMA3 | Proteasome subunit | ZNF418 | Zinc finger |
4 | PSMD3 | Proteasome subunit | KLF2 | Kruppel-like transcription factor |
5 | PSMB2 | Proteasome subunit | RGS18 | Regulator of G-protein signaling |
6 | VCP | AAA ATPase | PI3KCB | Phosphatidylinositol kinase |
7 | PSMB5 | Proteasome subunit | ZNF350 | Zinc finger |
8 | HSPA5 | Heat Shock Protein | ZNF67 | Zinc finger |
9 | CEBPG | Basic Leucine Zipper | ATP6V0A1 | V-ATPase |
10 | RYK | Type XV RTK | ACACA | Carboxylase |
Cell Line | Cell Line Properties | VLX1570 IC50 (nM) |
---|---|---|
KG1a | Complex karyotype [11], p53mut [29] | 307 ± 31 |
MOLM-14 | 49,<2n>,XY,+6,+8, ins(11;9)(q23;p22p23), del(14)(q13.2q31.3) fusion gene MLL-AF9 [30], p53wt [30,31] | 204 ± 73 |
HNT34 | 46,XX, t(3;3)(q21;q26), t(9;22)(q34;q11),20q− [32] | 273 ± 61 |
Kasumi-1 | Human hypodiploid karyotype—45,<2n>,X,−Y,−9,−13,−16, +3mar, t(8;21)(q22;q22), der(9)t(9;?)(p22;?), der(15)t(?9;15)((?q11;?p11) [33] | 260 ± 27 |
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Selvaraju, K.; Lotfi, K.; Gubat, J.; Miquel, M.; Nilsson, A.; Hill, J.; Jensen, L.D.; Linder, S.; D’Arcy, P. Sensitivity of Acute Myelocytic Leukemia Cells to the Dienone Compound VLX1570 Is Associated with Inhibition of the Ubiquitin-Proteasome System. Biomolecules 2021, 11, 1339. https://doi.org/10.3390/biom11091339
Selvaraju K, Lotfi K, Gubat J, Miquel M, Nilsson A, Hill J, Jensen LD, Linder S, D’Arcy P. Sensitivity of Acute Myelocytic Leukemia Cells to the Dienone Compound VLX1570 Is Associated with Inhibition of the Ubiquitin-Proteasome System. Biomolecules. 2021; 11(9):1339. https://doi.org/10.3390/biom11091339
Chicago/Turabian StyleSelvaraju, Karthik, Kourosh Lotfi, Johannes Gubat, Maria Miquel, Amanda Nilsson, Julia Hill, Lasse D. Jensen, Stig Linder, and Pádraig D’Arcy. 2021. "Sensitivity of Acute Myelocytic Leukemia Cells to the Dienone Compound VLX1570 Is Associated with Inhibition of the Ubiquitin-Proteasome System" Biomolecules 11, no. 9: 1339. https://doi.org/10.3390/biom11091339