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001-es BibID:BIBFORM114079
035-os BibID:(cikkazonosító)e64485 (WoS)001073487400016 (Scopus)85168335908
Első szerző:Guti Eliza (Molekuláris biológus)
Cím:High-Content Screening Assay for the Identification of Antibody-Dependent Cellular Cytotoxicity Modifying Compounds / Eliza Guti, Ákos Máté Bede, Csongor Váróczy, Csaba Hegedűs, Máté Á. Demény, László Virág
Dátum:2023
ISSN:1940-087X
Megjegyzések:Immunotherapy with antigen-specific antibodies or immune checkpoint inhibitors has revolutionized the therapy of breast cancer. Breast cancer cells expressing the epidermal growth factor receptor HER2 can be targeted by the anti-HER-2 antibody trastuzumab. Antibody-dependent cellular cytotoxicity (ADCC) is an important mechanism implicated in the antitumor action of HER-2. Trastuzumab bound to cancer cells can be recognized by the Fc receptors of ADCC effector cells (e.g., natural killer (NK) cells, macrophages, and granulocytes), triggering the cytotoxic activity of these immune cells leading to cancer cell death. We set out to develop an image-based assay for the quantification of ADCC to identify novel ADCC modulator compounds by high-content screening. In the assay, HER2 overexpressing JIMT-1 breast cancer cells are co-cultured with NK-92 cells in the presence of trastuzumab, and target cell death is quantified by automated microscopy and quantitative image analysis. Target cells are distinguished from effector cells based on their EGFP fluorescence. We show how compound libraries can be tested in the assay to identify ADCC modulator drugs. For this purpose, a compound library test plate was set up using randomly selected fine chemicals off the lab shelf. Three microtubule destabilizing compounds (colchicine, vincristine, podophyllotoxin) expected to interfere with NK cell migration and degranulation were also included in the test library. The test screen identified all three positive control compounds as hits proving the suitability of the method to identify ADCC-modifying drugs in a chemical library. With this assay, compound library screens can be performed to identify ADCC-enhancing compounds that could be used as adjuvant therapeutic agents for the treatment of patients receiving anticancer immunotherapies. In addition, the method can also be used to identify any undesirable ADCC-inhibiting side effects of therapeutic drugs taken by cancer patients for different indications.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Megjelenés:Journal of Visualized Experiments. - 198 (2023), p. 1-12. -
További szerzők:Bede Ákos Máté Váróczy Csongor Hegedűs Csaba (1980-) (biokémikus, molekuláris biológus) Demény Máté Ágoston (1976-) (molekuláris biológus) Virág László (1965-) (biokémikus, sejtbiológus, farmakológus)
Pályázati támogatás:GINOP-2.3.2-15-2016-00020
GINOP
GINOP-2.3.2-15-2016-00048
GINOP
Internet cím:Szerző által megadott URL
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2.

001-es BibID:BIBFORM100193
035-os BibID:(Scopus)85123488729 (WOS)000745777900001
Első szerző:Guti Eliza (Molekuláris biológus)
Cím:The multitargeted receptor tyrosine kinase inhibitor sunitinib induces resistance of HER2 positive breast cancer cells to trastuzumab-mediated ADCC / Guti Eliza, Regdon Zsolt, Sturniolo Isotta, Kiss Alexandra, Kovács Katalin, Demény Máté, Szöőr Árpád, Vereb György, Szöllősi János, Hegedűs Csaba, Polgár Zsuzsanna, Virág László
Dátum:2022
ISSN:0340-7004
Megjegyzések:Despite recent advances in the development of novel personalized therapies, breast cancer continues to challenge physicians with resistance to various advanced therapies. The anticancer action of the anti-HER2 antibody, trastuzumab, involves antibody-dependent cell-mediated cytotoxicity (ADCC) by natural killer (NK) cells. Here, we report a repurposing screen of 774 clinically used compounds on NK-cell + trastuzumab-induced killing of JIMT-1 breast cancer cells. Using a calceinbased high-content screening (HCS) assay for the image-based quantitation of ADCC that we have developed and optimized for this purpose, we have found that the multitargeted tyrosine kinase inhibitor sunitinib inhibits ADCC in this model. The cytoprotective effect of sunitinib was also confirmed with two other assays (lactate dehydrogenase release, and electric cell substrate impedance sensing, ECIS). The drug suppressed NK cell activation as indicated by reduced granzyme B deposition on to the target cells and inhibition of interferon-? production by the NK cells. Moreover, sunitinib induced downregulation of HER2 on the target cells' surface, changed the morphology and increased adherence of the target cells. Moreover, sunitinib also triggered the autophagy pathway (speckled LC3b) as an additional potential underlying mechanism of the cytoprotective effect of the drug. Sunitinib-induced ADCC resistance has been confirmed in a 3D tumor model revealing the prevention of apoptotic cell death (Annexin V staining) in JIMT-1 spheroids co-incubated with NK cells and trastuzumab. In summary, our HCS assay may be suitable for the facile identification of ADCC boosting compounds. Our data urge caution concerning potential combinations of ADCC-based immunotherapies and sunitinib.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Sunitinib
Natural killer cell
Breast cancer
ADCC
Trastuzumab
Herceptin
Megjelenés:Cancer Immunology Immunotherapy. - 71 : 9 (2022), p. 2151-2168. -
További szerzők:Regdon Zsolt (1988-) (biokémikus, molekuláris biológus) Sturniolo, Isotta Kiss Alexandra (1991-) (klinikai laboratóriumi kutató) Kovács Katalin (1978-) (biokémikus) Demény Máté Ágoston (1976-) (molekuláris biológus) Szöőr Árpád (1984-) (orvos) Vereb György (1965-) (biofizikus, orvos) Szöllősi János (1953-) (biofizikus) Hegedűs Csaba (1980-) (biokémikus, molekuláris biológus) Polgár Zsuzsanna (1978-) (agrármérnök, biotechnológus) Virág László (1965-) (biokémikus, sejtbiológus, farmakológus)
Pályázati támogatás:GINOP-2.3.3-15-2016-00020
GINOP
GINOP-2.3.2-15-2016-00048
GINOP
K132193
OTKA
K119690
OTKA
Internet cím:Szerző által megadott URL
DOI
Intézményi repozitóriumban (DEA) tárolt változat
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