Lipopolyamine treatment increases the efficacy of intoxication with saporin and an anticancer saporin conjugate

Saporin is a type I ribosome-inactivating protein that is often appended with a cell-binding domain to specifically target and kill cancer cells. Urokinase plasminogen activator (uPA)-saporin, for example, is an anticancer toxin that consists of a chemical conjugate between the human uPA and native...

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Veröffentlicht in:The FEBS journal 2007-09, Vol.274 (18), p.4825-4836
Hauptverfasser: Geden, Sandra E, Gardner, Richard A, Fabbrini, M. Serena, Ohashi, Masato, Phanstiel IV, Otto, Teter, Ken
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container_end_page 4836
container_issue 18
container_start_page 4825
container_title The FEBS journal
container_volume 274
creator Geden, Sandra E
Gardner, Richard A
Fabbrini, M. Serena
Ohashi, Masato
Phanstiel IV, Otto
Teter, Ken
description Saporin is a type I ribosome-inactivating protein that is often appended with a cell-binding domain to specifically target and kill cancer cells. Urokinase plasminogen activator (uPA)-saporin, for example, is an anticancer toxin that consists of a chemical conjugate between the human uPA and native saporin. Both saporin and uPA-saporin enter the target cell by endocytosis and must then escape the endomembrane system to reach the cytosolic ribosomes. The latter process may represent a rate-limiting step for intoxication and would therefore directly affect toxin potency. In the present study, we document two treatments (shock with dimethylsulfoxide and lipopolyamine coadministration) that generate substantial cellular sensitization to saporin/uPA-saporin. With the use of lysosome-endosome X (LEX)1 and LEX2 mutant cell lines, an endosomal trafficking step preceding cargo delivery to the late endosomes was identified as a major site for the dimethylsulfoxide-facilitated entry of saporin into the cytosol. Dimethylsulfoxide and lipopolyamines are known to disrupt the integrity of endosome membranes, so these reagents could facilitate the rapid movement of toxin from permeabilized endosomes to the cytosol. However, the same pattern of toxin sensitization was not observed for dimethylsulfoxide- or lipopolyamine-treated cells exposed to diphtheria toxin, ricin, or the catalytic A chain of ricin. The sensitization effects were thus specific for saporin, suggesting a novel mechanism of saporin translocation by endosome disruption. Lipopolyamines have been developed as in vivo gene therapy vectors; thus, lipopolyamine coadministration with uPA-saporin or other saporin conjugates could represent a new approach for anticancer toxin treatments.
doi_str_mv 10.1111/j.1742-4658.2007.06008.x
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The sensitization effects were thus specific for saporin, suggesting a novel mechanism of saporin translocation by endosome disruption. Lipopolyamines have been developed as in vivo gene therapy vectors; thus, lipopolyamine coadministration with uPA-saporin or other saporin conjugates could represent a new approach for anticancer toxin treatments.</abstract><cop>Oxford, UK</cop><pub>Oxford, UK : Blackwell Publishing Ltd</pub><pmid>17714513</pmid><doi>10.1111/j.1742-4658.2007.06008.x</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record>
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subjects Animals
anticancer therapy
Antineoplastic Agents - chemistry
Antineoplastic Agents - toxicity
Cancer
Cell Line
Chemotherapy
CHO Cells
Cold Temperature
Cricetinae
Cricetulus
Dimethyl Sulfoxide - pharmacology
Dimethyl Sulfoxide - toxicity
Endocytosis
Endocytosis - drug effects
Endoplasmic Reticulum - drug effects
Endoplasmic Reticulum - metabolism
endosome
Endosomes - metabolism
intracellular trafficking
Lysosomes - metabolism
Molecular biology
plant ribosome‐inactivating protein
polyamine
Polyamines - pharmacology
Proteins
Ribosome Inactivating Proteins, Type 1 - chemistry
Ribosome Inactivating Proteins, Type 1 - toxicity
Ricin - toxicity
Toxins
Urokinase-Type Plasminogen Activator - chemistry
Urokinase-Type Plasminogen Activator - toxicity
title Lipopolyamine treatment increases the efficacy of intoxication with saporin and an anticancer saporin conjugate
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