Intracellular route and mechanism of action of ERB-hRNase, a human anti-ErbB2 anticancer immunoagent.
Human anti-ErbB2 immunoRNase with Erbicin fused to HP-RNase (ERB-hRNase) is a fully human immunoRNase made up of human pancreatic RNase fused to a human anti-ErbB2 scFv. It binds selectively with high affinity to ErbB2-positive cells, and specifically inhibits their proliferation, in vitro and in vivo. An investigation of its mechanism of action and its intracellular destination has revealed that ERB-hRNase depends on its RNase activity for cytotoxic action; it reaches the cytosol directly from the endosomal compartment; it is inhibited by the cytosolic RNase inhibitor (cRI), but the levels that ERB-hRNase reaches in the cytosol neutralize cRI, thus inducing cell death by apoptosis.
De Lorenzo
Claudia
C
Dipartimento di Biologia Strutturale e Funzionale, Università di Napoli Federico II, via Cinthia, 80126 Napoli, Italy.
Di Malta
Chiara
C
Calì
Gaetano
G
Troise
Fulvia
F
Nitsch
Lucio
L
D'Alessio
Giuseppe
G
D000970:Antineoplastic Agents / Q000032:analysis / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D017209:Apoptosis; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D003600:Cytosol / Q000201:enzymology; D004791:Enzyme Inhibitors; D006801:Humans; D000922:Immunotoxins / Q000032:analysis / Q000494:pharmacology*; D012313:RNA / Q000187:drug effects / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011993:Recombinant Fusion Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D012260:Ribonucleases / Q000032:analysis / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000922:Immunotoxins; D012313:RNA; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D012260:Ribonucleases; C518070:ERB-hRNase