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1.

001-es BibID:BIBFORM073532
Első szerző:Barok Márk (biofizikus)
Cím:Cancer-derived exosomes from HER2-positive cancer cells carry trastuzumab-emtansine into cancer cells leading to growth inhibition and caspase activation / Mark Barok, Maija Puhka, Gyorgy Vereb, Janos Szollosi, Jorma Isola, Heikki Joensuu
Dátum:2018
ISSN:1471-2407
Megjegyzések:Background: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that carries a cytotoxic drug (DM1) toHER2-positive cancer. The target of T-DM1 (HER2) is present also on cancer-derived exosomes. We hypothesizedthat exosome-bound T-DM1 may contribute to the activity of T-DM1.Methods: Exosomes were isolated from the cell culture medium of HER2-positive SKBR-3 and EFM-192A breast cancercells, HER2-positive SNU-216 gastric cancer cells, and HER2-negative MCF-7 breast cancer cells by serial centrifugationsincluding two ultracentrifugations, and treated with T-DM1. T-DM1 not bound to exosomes was removed using HER2-coated magnetic beads. Exosome samples were analyzed by electron microscopy, flow cytometry and Westernblotting. Binding of T-DM1-containing exosomes to cancer cells and T-DM1 internalization were investigated withconfocal microscopy. Effects of T-DM1-containg exosomes on cancer cells were investigated with the AlamarBluecell proliferation assay and the Caspase-Glo 3/7 caspase activation assay.Results: T-DM1 binds to exosomes derived from HER2-positive cancer cells, but not to exosomes derived fromHER2-negative MCF-7 cells. HER2-positive SKBR-3 cells accumulated T-DM1 after being treated with T-DM1-containgexosomes, and treatment of SKBR-3 and EFM-192A cells with T-DM1-containing exosomes resulted in growth inhibitionand activation of caspases 3 and/or 7.Conclusion: T-DM1 binds to exosomes derived from HER2-positive cancer cells, and T-DM1 may be carried toother cancer cells via exosomes leading to reduced viability of the recipient cells. The results suggest a new mechanismof action for T-DM1, mediated by exosomes derived from HER2-positive cancer.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Breast cancer
Trastuzumab-emtansine
T-DM1
HER2
Exosome
Megjelenés:Bmc Cancer. - 18 : 1 (2018), p. 504-516. -
További szerzők:Puhka, Maija Vereb György (1965-) (biofizikus, orvos) Szöllősi János (1953-) (biofizikus) Isola, Jorma Joensuu, Heikki
Pályázati támogatás:GINOP-2.3.2-15-2016-00020
GINOP
GINOP-2.3.2-15-2016-00050
GINOP
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2.

001-es BibID:BIBFORM005174
035-os BibID:(scopus)38349044364 (wos)000253278400023
Első szerző:Barok Márk (biofizikus)
Cím:Trastuzumab decreases the number of circulating and disseminated tumor cells despite trastuzumab resistance of the primary tumor / Márk Barok, Margit Balázs, Péter Nagy, Zsuzsa Rákosy, Andrea Treszl, Enikő Tóth, István Juhász, John W. Park, Jorma Isola, György Vereb, János Szöllősi
Dátum:2008
ISSN:304-3835 (Print)
Megjegyzések:We have recently shown that despite of the fact that the ErbB2-positive JIMT-1 human breast cancer cells intrinsically resistant to trastuzumab in vitro, trastuzumab inhibited the outgrowth of early phase JIMT-1 xenografts in SCID mice via antibody-dependent cellular cytotoxicity (ADCC). Here we show that trastuzumab significantly reduces the number of circulating and disseminated tumor cells (CTCs and DTCs) in this xenograft model system at a time when the primary tumor is already unresponsive to trastuzumab. This observation suggests that ErbB2 positive CTCs and DTCs might be sensitive to trastuzumab-mediated ADCC even if when the primary tumor is already non-responsive. Thus, trastuzumab treatment might also be beneficial in the case of patients with breast cancer that is already trastuzumab resistant.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
analysis
Animals
antagonists and inhibitors
Antibodies
Antibodies, Monoclonal
Antigens
Antigens, CD45
Antineoplastic Agents
article
Biophysics
blood
Bone Marrow
Breast Neoplasms
Cell Line, Tumor
Cells
Chromosomes, Human,X
drug effects
Drug Resistance, Neoplasm
drug therapy
EGFR
Epidermal Growth Factor
ErbB2
Female
genetics
Histocompatibility Antigens
Histocompatibility Antigens Class I
Human
Humans
Hungary
Immunohistochemistry
immunology
In Situ Hybridization,Fluorescence
In Vitro
metabolism
Mice
Mice, Scid
mouse
Neoplasm Circulating Cells
Neoplasm Metastasis
pathology
pharmacology
Receptor, Epidermal Growth Factor
Research
Research Support
Support
therapeutic use
Time Factors
Trastuzumab resistance
Xenograft Model Antitumor Assays
egyetemen (Magyarországon) készült közlemény
Megjelenés:Cancer Letters. - 260 : 1-2 (2008), p. 198-208. -
További szerzők:Balázs Margit (1952-) (sejtbiológus, molekuláris genetikus) Nagy Péter (1971-) (biofizikus) Rákosy Zsuzsa (1978-) (sejtbiológus, molekuláris biológus, genetikus) Treszl Andrea (1974-) (molekuláris biológus) Tóth Enikő Juhász István (1956-) (bőrgyógyász, bőrsebész, kozmetológus, klinikai onkológus) Park, John W. Isola, Jorma Vereb György (1965-) (biofizikus, orvos) Szöllősi János (1953-) (biofizikus)
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3.

001-es BibID:BIBFORM001053
035-os BibID:(scopus)34447298092 (wos)000248154300017
Első szerző:Barok Márk (biofizikus)
Cím:Trastuzumab causes antibody-dependent cellular cytotoxicity-mediated growth inhibition of submacroscopic JIMT-1 breast cancer xenografts despite intrinsic drug resistance / Barok M., Isola J., Pályi-Krekk Zs., Nagy P., Juhász I., Vereb Gy., Kauraniemi P., Kapanen A., Tanner M., Vereb Gy., Szöllősi J.
Dátum:2007
Megjegyzések:Trastuzumab is a recombinant antibody drug that is widely used for the treatment of breast cancer. Despite encouraging clinical results, some cancers are primarily resistant to trastuzumab, and a majority of those initially responding become resistant during prolonged treatment. The mechanisms of trastuzumab resistance have not been fully understood. We examined the role of antibody-dependent cellular cytotoxicity (ADCC) using JIMT-1 cells that are ErbB2 positive but intrinsically resistant to trastuzumab in vitro. Unexpectedly, in experiments mimicking adjuvant therapy of submacroscopic disease in vivo (JIMT-1 cells inoculated s.c. in severe combined immunodeficiency mice), trastuzumab was able to inhibit the outgrowth of macroscopically detectable xenograft tumors for up to 5-7 weeks. The effect is likely to be mediated via ADCC because trastuzumab-F(ab')(2) was ineffective in this model. Moreover, in vitro ADCC reaction of human leukocytes was equally strong against breast cancer cells intrinsically sensitive (SKBR-3) or resistant (JIMT-1) to trastuzumab or even against a subline of JIMT-1 that was established from xenograft tumors growing despite trastuzumab treatment. These results suggest that ADCC may be the predominant mechanism of trastuzumab action on submacroscopic tumor spread. Thus, measuring the ADCC activity of patient's leukocytes against the tumor cells may be a relevant predictor of clinical trastuzumab responsiveness in vivo.
Tárgyszavak:Orvostudományok Természettudományok Elméleti orvostudományok Biológiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
ErbB2 receptor
trastuzumab
breast cancer
antibody therapy
Megjelenés:Molecular Cancer Therapeutics. - 6 : 7 (2007), p. 2065-2072. -
További szerzők:Isola, Jorma Pályiné Krekk Zsuzsanna (1974-) (molekuláris biológus) Nagy Péter (1971-) (biofizikus) Juhász István (1956-) (bőrgyógyász, bőrsebész, kozmetológus, klinikai onkológus) Vereb György (1938-) (biokémikus, sejtbiológus) Kauraniemi, Päivikki Kapanen, Anita I. Tanner, Minna Vereb György (1965-) (biofizikus, orvos) Szöllősi János (1953-) (biofizikus)
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4.

001-es BibID:BIBFORM042484
035-os BibID:(scopus)23844475901 (wos)000231845600013
Első szerző:Mocanu, Maria-Magdalena
Cím:Associations of ErbB2, beta1-integrin and lipid rafts on Herceptin (Trastuzumab) resistant and sensitive tumor cell lines / Maria-Magdalena Mocanu, Zsolt Fazekas, Miklós Petrás, Péter Nagy, Zsolt Sebestyén, Jorma Isola, József Tímár, John W. Park, György Vereb, János Szöllősi
Dátum:2005
ISSN:0304-3835
Megjegyzések:ErbB2-mediated transmembrane signaling is a key target of novel anticancer agents such as Herceptin. Our comparison of Herceptin resistant (JIMT-1, MKN-7) and sensitive (SKBR-3, N-87) cell lines demonstrates the importance of ErbB2 association patterns involving integrins and lipid rafts. Flow cytometric FRET and confocal microscopic measurements revealed colocalization and molecular proximity between b1-integrins and ErbB2, as well as their association with lipid rafts. A weak functional interaction between ErbB2 and b1-integrin and the fact that ErbB2 did not co-patch with b1-integrins uponcrosslinking imply that ErbB2 and b1-integrin define two distinct molecular association clusters from a functional point of view. Although Herceptin-sensitive cell lines expressed more ErbB2 and fewer b1-integrin molecules on their surface than their resistant counterparts, this finding probably does not explain the Herceptin resistant phenotype due to the weak interaction between b1-integrins and ErbB2. Our results imply that the true significance of the expression profile of proteins involved inoncogenesis can only be understood after characterizing their molecular interactions.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Antibodies
Antibodies,Monoclonal
Antigens,CD29
Biophysics
Breast Neoplasms
Cell Line
Cell Membrane
Drug Resistance,Neoplasm
Humans
Hungary
Membrane Microdomains
metabolism
pathology
pharmacology
Phenotype
physiology
Proteins
Receptor,erbB-2
Research
Support
Tumor Cells,Cultured
egyetemen (Magyarországon) készült közlemény
Megjelenés:Cancer Letters. - 227 : 2 (2005), p. 201-212. -
További szerzők:Fazekas Zsolt (1971-) (biofizikus) Petrás Miklós (1977-) (orvos) Nagy Péter (1971-) (biofizikus) Sebestyén Zsolt Isola, Jorma Timár József Park, John W. Vereb György (1965-) (biofizikus, orvos) Szöllősi János (1953-) (biofizikus)
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5.

001-es BibID:BIBFORM002762
035-os BibID:(scopus)35448969823 (wos)000251600200021
Első szerző:Pályiné Krekk Zsuzsanna (molekuláris biológus)
Cím:Hyaluronan-induced masking of ErbB2 and CD44-enhanced trastuzumab internalisation in trastuzumab resistant breast cancer / Palyi-Krekk Z., Barok M., Isola J., Tammi M., Szollosi J., Nagy P.
Dátum:2007
Megjegyzések:Although trastuzumab, a recombinant humanised anti-ErbB2 antibody, is widely used in the treatment of breast cancer, neither its mechanism of action, nor the factors leading to resistance are fully understood. We have previously shown that antibody-dependent cellular cytotoxicity is pivotal in the in vivo effect of trastuzumab against JIMT-1, a cell line showing in vitro resistance to the antibody, and suggested that masking of the trastuzumab-binding epitope by MUC-4, a cell surface mucin, took place. Here, we further explored the role of masking of ErbB2 in connection with CD44 expression and synthesis of its ligand, hyaluronan. We show that high expression of CD44 observed in JIMT-1 cells correlates with ErbB2 downregulation in vivo, while siRNA-mediated inhibition of CD44 expression leads to decreased rate of trastuzumab internalisation and low cell proliferation in vitro. An inhibitor of hyaluronan synthesis, 4-methylumbelliferon (4-MU) significantly reduced the hyaluronan level of JIMT-1 cells both in vivo and in vitro leading to enhanced binding of trastuzumab to ErbB2 and increased ErbB2 down-regulation. Furthermore, the inhibitory effect of trastuzumab on the growth of JIMT-1 xenografts was significantly increased by 4-MU treatment. Our results point to the importance of the CD44-hyaluronan pathway in the escape of tumour cells from receptor-oriented therapy
Tárgyszavak:Természettudományok Biológiai tudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Antibodies
Biophysics
Cell Line
Cell Proliferation
Cells
Down-Regulation
Hungary
In Vitro
therapy
Megjelenés:European Journal of Cancer. - 43 : 16 (2007), p. 2423-2433. -
További szerzők:Barok Márk (1976-) (biofizikus) Isola, Jorma Tammi, Markku (kutatóorvos) Szöllősi János (1953-) (biofizikus) Nagy Péter (1971-) (biofizikus)
Internet cím:elektronikus változat
DOI
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6.

001-es BibID:BIBFORM102341
Első szerző:Tufeanu, Maria Magdalena
Cím:Association of erbb2, [beta]1 integrin and lipid rafts on tumor cells / Tufeanu M. M., Fazekas Z., Petrás M., Isola J., Vereb G., Szöllősi J.
Dátum:2004
ISSN:0196-4763
Tárgyszavak:Orvostudományok Elméleti orvostudományok idézhető absztrakt
folyóiratcikk
Megjelenés:Cytometry. - 59A : 1 (2004), p. 79. -
További szerzők:Fazekas Zsolt (1971-) (biofizikus) Petrás Miklós (1977-) (orvos) Isola, Jorma Vereb György (1965-) (absztraktok, könyvfejezetek) Szöllősi János (1953-) (biofizikus)
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7.

001-es BibID:BIBFORM102343
Első szerző:Zsebik Barbara (biofizikus)
Cím:ErbB2 homodimerization and activation in Herceptin resistant and sensitive cell lines / Zsebik B., Petrás M., Isola J., Szöllősi J., Vereb G.
Dátum:2004
ISSN:0196-4763
Tárgyszavak:Orvostudományok Elméleti orvostudományok idézhető absztrakt
folyóiratcikk
Megjelenés:Cytometry. - 59A : 1 (2004), p. 113. -
További szerzők:Petrás Miklós (1977-) (orvos) Isola, Jorma Szöllősi János (1953-) (biofizikus) Vereb György (1965-) (absztraktok, könyvfejezetek)
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8.

001-es BibID:BIBFORM005110
035-os BibID:(scopus)33644694046 (wos)000236477900020
Első szerző:Zsebik Barbara (biofizikus)
Cím:Hsp90 inhibitor 17-AAG reduces ErbB2 levels and inhibits proliferation of the trastuzumab resistant breast tumor cell line JIMT-1 / Zsebik, B., Citri, A., Isola, J., Yarden, Y., Szollosi, J., Vereb, G.
Dátum:2006
ISSN:165-2478 (Print)
Megjegyzések:ErbB2, a member of the EGF receptor family of tyrosine kinases is overexpressed on many tumor cells of epithelial origin and is the molecular target of trastuzumab (Herceptin), the first humanized antibody used in the therapy of solid tumors. Trastuzumab, which is thought to act, at least in part, by downregulating ErbB2 expression is only effective in approximately 30-40% of ErbB2 positive breast tumors. Geldanamycin and its derivative 17-AAG are potential antitumor agents capable of downregulating client proteins of Hsp90, including ErbB2. To investigate the ability of 17-AAG to downregulate ErbB2 in trastuzumab resistant breast cancer cells and the possibility of 17-AAG and trastuzumab potentiating each other's effect, the recently established trastuzumab resistant breast cancer cell line, JIMT-1 was compared to the known trastuzumab sensitive SKBR-3 line. Baseline and stimulus-evoked dimerization and activation levels of ErbB2, and the effects of trastuzumab and 17-AAG alone and in combination on cell proliferation and apoptosis, as well as on ErbB2 expression and phosphorylation have been measured. Baseline activation and amenability to activation and downregulation by trastuzumab was much lower in the resistant line. However, 17-AAG enhanced ErbB2 homodimerization after 5-10 min of treatment in both cell lines, and decreased proliferation with an IC50 of 70 nM for SKBR-3 and 10nM for JIMT-1. Thus, 17-AAG may be a useful drug in trastuzumab resistant ErbB2 overexpressing tumors. The antiproliferative effect of 17-AAG was positively correlated with phosphorylation and downregulation of ErbB2 and was dominated by apoptosis, although, especially at higher doses, necrosis was also present. Interestingly, IC50 values for ErbB2 downregulation and phosphorylation, in the 30-40 nM range, were not significantly different for the two cell lines. This observation and the negative correlation between resting ErbB2 levels and the antiproliferative effect of 17-AAG may indicate that activation of ErbB2 to some extent could counteract the overall cytostatic effect, especially at higher levels of ErbB2 expression. The usual therapeutic dose of trastuzumab did not change the IC50 of 17-AAG on the proliferation of either cell line, but nevertheless decreased overall ErbB2 phosphorylation and at low doses of 17-AAG further decreased cell growth in the sensitive SKBR-3, thus trastuzumab may be a good combination partner to counteract undesired activating effects of 17-AAG.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
analogs and derivatives
antagonists and inhibitors
Antibodies
Antibodies,Monoclonal
Antineoplastic Agents
Apoptosis
Benzoquinones
Biophysics
Breast Neoplasms
Cell Line
Cell Line,Tumor
Cell Proliferation
Cells
Dimerization
drug effects
Drug Resistance,Neoplasm
drug therapy
enzymology
HSP90 Heat-Shock Proteins
Humans
Hungary
Lactams,Macrocyclic
metabolism
Necrosis
pharmacology
Phosphorylation
Protein Kinase Inhibitors
Proteins
Receptor,erbB-2
Research
Rifabutin
Support
therapeutic use
therapy
Megjelenés:Immunology Letters. - 104 : 1-2 (2006), p. 146-155. -
További szerzők:Citri, Ami Isola, Jorma Yarden, Yosef Szöllősi János (1953-) (biofizikus) Vereb György (1965-) (biofizikus, orvos)
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