EP4 receptor agonist L-902688 augments cytotoxic activities of ibrutinib, idelalisib, and venetoclax against chronic lymphocytic leukemia cells

Nabergoj, Sanja; Markovič, Tijana; Avsec, Damjan; Gobec, Martina; Podgornik, Helena; Mlinarič-Raščan, Irena

doi:10.1016/j.bcp.2020.114352

Cited by 4 publications

(7 citation statements)

References 66 publications

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“…CLL samples had prognostically good as well as poor genetic lesions: 16/24 had del(13q), 3/24 had trisomy 12, 4/24 had del(11q), 3/24 had del(17p), and 5/17 had mutated immunoglobulin heavy-chain variable region (IGHV) gene ( Table 1 ). The patient CLL cells were isolated from whole blood using the RosetteSep Human B Cell Enrichment Cocktail (Stem Cell Technologies, Vancouver, BC, Canada), as described previously [ 22 ]. Peripheral blood mononuclear cells (PBMCs) of healthy donors were also isolated as described previously [ 22 ].…”

Section: Methodsmentioning

confidence: 99%

“…The patient CLL cells were isolated from whole blood using the RosetteSep Human B Cell Enrichment Cocktail (Stem Cell Technologies, Vancouver, BC, Canada), as described previously [ 22 ]. Peripheral blood mononuclear cells (PBMCs) of healthy donors were also isolated as described previously [ 22 ]. Both primary CLL cells and PBMCs were maintained at 1–2 × 10 6 cells/mL in RPMI1640 medium, supplemented with 10% heat-inactivated fetal bovine serum, 2 mM L-glutamine, 100 U/mL penicillin, and 100 µg/mL streptomycin.…”

Section: Methodsmentioning

confidence: 99%

“…The cell cycle analysis was performed in a step by step approach as described previously [ 22 ]. The proportions of the cells in each phase of the cell cycle were determined using Watson’s pragmatic model.…”

Section: Methodsmentioning

confidence: 99%

“…Apoptosis of primary CLL cells was assessed by determination of the levels of phosphatidylserine exposure using R-phycoerythrin conjugated annexin V (R-PE Annexin V; Invitrogen, Carlsbad, CA, USA) and the nucleic acid stain SYTOX Blue Dead Cell Stain (Invitrogen, Carlsbad, CA, USA), following manufacturer instructions, and as described previously [ 22 ]. Briefly, patient-derived CLL cells (1 × 10 6 cells/mL) were treated with the indicated compounds for 24 h. Then, the cells were harvested, washed with cold PBS, and resuspended in the annexin-binding buffer to a final concentration of 1 × 10 6 cells/mL.…”

Section: Methodsmentioning

confidence: 99%

“…SDS-PAGE and Western blotting were carried out as described previously [ 22 ]. The anti-p62/SQSTM1 (#CY-88588) antibody was from Cell Signaling Technology (Danvers, MA, USA).…”

Section: Methodsmentioning

confidence: 99%

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Targeting Autophagy Triggers Apoptosis and Complements the Action of Venetoclax in Chronic Lymphocytic Leukemia Cells

Avsec

Djordjevič

Kandušer

et al. 2021

Cancers

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Continuous treatment of patients with chronic lymphocytic leukemia (CLL) with venetoclax, an antagonist of the anti-apoptotic protein Bcl-2, can result in resistance, which highlights the need for novel targets to trigger cell death in CLL. Venetoclax also induces autophagy by perturbing the Bcl-2/Beclin-1 complex, so autophagy might represent a target in CLL. Diverse autophagy inhibitors were assessed for cytotoxic activities against patient-derived CLL cells. The AMPK inhibitor dorsomorphin, the ULK1/2 inhibitor MRT68921, and the autophagosome–lysosome fusion inhibitor chloroquine demonstrated concentration-dependent and time-dependent cytotoxicity against CLL cells, even in those from hard-to-treat patients who carried del(11q) and del(17p). Dorsomorphin and MRT68921 but not chloroquine triggered caspase-dependent cell death. According to the metabolic activities of CLL cells and PBMCs following treatments with 10 µM dorsomorphin (13% vs. 84%), 10 µM MRT68921 (7% vs. 78%), and 25 µM chloroquine (41% vs. 107%), these autophagy inhibitors are selective toward CLL cells. In these CLL cells, venetoclax induced autophagy, and addition of dorsomorphin, MRT68921, or chloroquine showed potent synergistic cytotoxicities. Additionally, MRT68921 alone induced G2 arrest, but when combined with venetoclax, it triggered caspase-dependent cytotoxicity. These data provide the rationale to target autophagy and for autophagy inhibitors as potential treatments for patients with CLL.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…SDS-PAGE and Western blotting were carried out as described previously [ 22 ]. The anti-p62/SQSTM1 (#CY-88588) antibody was from Cell Signaling Technology (Danvers, MA, USA).…”

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Targeting Autophagy Triggers Apoptosis and Complements the Action of Venetoclax in Chronic Lymphocytic Leukemia Cells

Avsec

Djordjevič

Kandušer

et al. 2021

Cancers

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Inhibition of p38 MAPK or immunoproteasome overcomes resistance of chronic lymphocytic leukemia cells to Bcl-2 antagonist venetoclax

et al. 2022

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Chronic lymphocytic leukemia (CLL) is a hematological neoplasm of CD19-positive mature-appearing B lymphocytes. Despite the clinical success of targeted therapies in CLL, the development of resistance diminishes their therapeutic activity. This is also true for the Bcl-2 antagonist venetoclax. We investigated the molecular mechanisms that drive venetoclax resistance in CLL, with a clear focus to provide new strategies to successfully combat it. Activation of CLL cells with IFNγ, PMA/ionomycin, and sCD40L diminished the cytotoxicity of venetoclax. We demonstrated that the metabolic activity of cells treated with 1 nM venetoclax alone was 48% of untreated cells, and was higher for cells co-treated with IFNγ (110%), PMA/ionomycin (78%), and sCD40L (62%). As of molecular mechanism, we showed that PMA/ionomycin and sCD40L triggered translocation of NFκB in primary CLL cells, while IFNγ activated p38 MAPK, suppressed spontaneous and venetoclax-induced apoptosis and induced formation of the immunoproteasome. Inhibition of immunoproteasome with ONX-0914 suppressed activity of immunoproteasome and synergized with venetoclax against primary CLL cells. On the other hand, inhibition of p38 MAPK abolished cytoprotective effects of IFNγ. We demonstrated that venetoclax-resistant (MEC-1 VER) cells overexpressed p38 MAPK and p-Bcl-2 (Ser70), and underexpressed Mcl-1, Bax, and Bak. Inhibition of p38 MAPK or immunoproteasome triggered apoptosis in CLL cells and overcame the resistance to venetoclax of MEC-1 VER cells and venetoclax-insensitive primary CLL cells. In conclusion, the p38 MAPK pathway and immunoproteasome represent novel targets to combat venetoclax resistance in CLL.

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EP4 receptor agonist CAY10598 upregulates ROS-dependent Hsp90 cleavage in colorectal cancer cells

Chae,

Jung,

Kim

et al. 2024

Free Radical Research

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EP4 receptor agonist L-902688 augments cytotoxic activities of ibrutinib, idelalisib, and venetoclax against chronic lymphocytic leukemia cells

Cited by 4 publications

References 66 publications

Targeting Autophagy Triggers Apoptosis and Complements the Action of Venetoclax in Chronic Lymphocytic Leukemia Cells

Targeting Autophagy Triggers Apoptosis and Complements the Action of Venetoclax in Chronic Lymphocytic Leukemia Cells

Inhibition of p38 MAPK or immunoproteasome overcomes resistance of chronic lymphocytic leukemia cells to Bcl-2 antagonist venetoclax

EP4 receptor agonist CAY10598 upregulates ROS-dependent Hsp90 cleavage in colorectal cancer cells

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