Összesen 2 találat.


001-es BibID:BIBFORM100193
035-os BibID:(Scopus)85123488729 (WOS)000745777900001
Első szerző:Guti Eliza
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
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
Natural killer cell
Breast cancer
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
Internet cím:Szerző által megadott URL
Intézményi repozitóriumban (DEA) tárolt változat


001-es BibID:BIBFORM090173
Első szerző:Regdon Zsolt (biokémikus, molekuláris biológus)
Cím:High-Content Screening identifies inhibitors of oxidative stress-induced parthanatos : cytoprotective and anti-inflammatory effects of ciclopirox / Regdon Zsolt, Demény Máté A., Kovács Katalin, Hajnády Zoltán, Nagy-Pénzes Máté, Bakondi Edina, Kiss Alexandra, Hegedűs Csaba, Virág László
Megjegyzések:Background and purpose: Excessive oxidative stress can induce poly (ADP-ribose) polymerase-1 (PARP1)-mediated, programmed necrotic cell death, termed parthanatos. Inhibition of parthanatos may be therapeutically beneficial in a wide array of diseases associated with tissue injury and inflammation. Our goal was to identify novel molecules inhibiting parthanatos. Experimental approach: A small library of 774 pharmacologically active compounds was screened in a Sytox green uptake assay which identified 20 hits that reduced hydrogen peroxide-induced parthanatos with an efficiency comparable to the benchmark PARP inhibitor, PJ34. Key results: Of these hits, two compounds, antifungal ciclopirox (CIP) and dopaminergic agonist apomorphine (AMO) inhibited PAR polymer synthesis. These two compounds prevented the binding of PARP1 to oxidatively damaged DNA but did not directly interfere with the interaction between DNA and PARP1. Both compounds inhibited mitochondrial superoxide and H2 O2 production and suppressed DNA breakage. Since H2 O2 -induced damage is dependent on Fe2+ -catalysed hydroxyl radical production (Fenton chemistry), we determined the iron chelation activity of the two test compounds and found that CIP and, to a lesser extent, AMO act as iron chelators. We also show that the Fe2+ chelation and indirect PARP inhibitory effects of CIP translate to anti-inflammatory actions as demonstrated in a mouse dermatitis model, where CIP reduced ear swelling, inflammatory cell recruitment, and poly (ADP-ribosyl)ation. Conclusion and implications: Our findings indicate that the antimycotic drug, CIP, acts as an iron chelator and thus targets an early event in hydrogen-peroxide-induced parthanatos. CIP has the potential to be repurposed as a cytoprotective and anti-inflammatory agent.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
cell death
oxidative stress
poly (ADP-ribose) polymerase 1
regulated necrosis
Megjelenés:British Journal Of Pharmacology. - 2021 (2021), p. 1-19. -
További szerzők:Demény Máté Ágoston (1976-) (molekuláris biológus) Kovács Katalin (1978-) (biokémikus) Hajnády Zoltán (1991-) (biomérnök, biokémikus) Nagy-Pénzes Máté (1988-) (biokémikus) Bakondi Edina (1975-) (biokémikus, vegyész) Kiss Alexandra (1991-) (klinikai laboratóriumi kutató) Hegedűs Csaba (1980-) (biokémikus, molekuláris biológus) Virág László (1965-) (biokémikus, sejtbiológus, farmakológus)
Pályázati támogatás:GINOP-2.3.2-15-2016-00048-STAYALIVE
GINOP-2.3.2-15-2016-00020 TUMORDNS"
OTKA K132193
OTKA K112336
Internet cím:Szerző által megadott URL
Intézményi repozitóriumban (DEA) tárolt változat
Rekordok letöltése1