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Verfasst von:Geis, Nicolas [VerfasserIn]   i
 Zell, Stefanie [VerfasserIn]   i
 Rutz, Renate [VerfasserIn]   i
 Li, Wenhan [VerfasserIn]   i
 Giese, Thomas [VerfasserIn]   i
 Mamidi, Srinivas [VerfasserIn]   i
 Schultz, Stefan [VerfasserIn]   i
 Kirschfink, Michael [VerfasserIn]   i
Titel:Inhibition of membrane complement inhibitor expression (CD46, CD55, CD59) by siRNA sensitizes tumor cells to complement attack in vitro
Verf.angabe:Nicolas Geis, Stefanie Zell, Renate Rutz, Wenhan Li, Thomas Giese, Srinivas Mamidi, Stefan Schultz and Michael Kirschfink
Jahr:2010
Umfang:10 S.
Teil:volume:10
 year:2010
 number:8
 pages:922-931
 extent:10
Fussnoten:Gesehen am 21.06.2021
Titel Quelle:Enthalten in: Current cancer drug targets
Ort Quelle:Hilversum [u.a.] : Bentham Science Publ., 2001
Jahr Quelle:2010
Band/Heft Quelle:10(2010), 8, Seite 922-931
ISSN Quelle:1873-5576
Abstract:The efficacy of cancer-immunotherapy with complement-activating monoclonal antibodies is limited by over-expression of one or more membrane-bound complement regulatory proteins (mCRPs: CD46, CD55, CD59) on the surface of neoplastic cells. In this study we designed small interfering RNAs (siRNAs) for posttranscriptional gene knock down of CD46, CD55 and CD59 aiming at to sensitize tumor cells to complement attack and thereby to better exploit complement for tumor cell destruction. Tumor cell lines of different origin, such as Du145 (prostate), BT474 (breast) and K562 (erythroleukemia) were selected for the study. FACS-analysis demonstrated that siRNA anti-CD46(301) reduced CD46 protein expression up to 80%, siRNA anti-CD55(255) diminished CD55 protein expression up to 49%, and CD59 protein expression was inhibited up to 82% by siRNA anti-CD59(1339). Time course experiments revealed a long-lasting silencing effect with >50% complement regulator inhibition up to day 13. Upon mCRP knock down, complement-dependent cytotoxicity (CDC) was augmented by 20-30% for CD46, by up to 24% for CD55 and by up to 55% for CD59. The combined inhibition of all three inhibitors further enhanced CDC by up to 66%. Dependent on the cell line, CD46 and CD55 downregulation increased significantly C3 ospsonization, which is known to support cell-mediated defense mechanisms. mCRP blocking antibodies were only partly able to further augment the tumor cells' susceptibility to complement lysis. Thus, siRNA-induced inhibition of complement regulator expression clearly sensitizes malignant cells to complement attack and, if specifically targeted to the tumor, appears suited as adjuvant to improve antibody-based cancer immunotherapy.
DOI:doi:10.2174/156800910793357952
URL:Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.

Volltext: https://dx.doi.org/10.2174/156800910793357952
 DOI: https://doi.org/10.2174/156800910793357952
Datenträger:Online-Ressource
Sprache:eng
Sach-SW:CD55 Antigens
 CD59 Antigens
 Complement Activation
 Flow Cytometry
 Humans
 Membrane Cofactor Protein
 Neoplasms
 Reverse Transcriptase Polymerase Chain Reaction
 RNA, Messenger
 RNA, Neoplasm
 RNA, Small Interfering
 Tumor Cells, Cultured
K10plus-PPN:1760900826
Verknüpfungen:→ Zeitschrift

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