Potentiation of ribonuclease cytotoxicity by a poly(amidoamine) dendrimer

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:21

Article

Ellis, Gregory A.¹  Hornung, Megan L.²  Raines, Ronald T.^1,3 

[1] Univ Wisconsin, Dept Biochem, Madison, WI 53706 USA

[2] Univ Wisconsin, Dept Zool, Madison, WI 53706 USA

[3] Univ Wisconsin, Dept Chem, Madison, WI 53706 USA

关键词: Cancer;    Dendrimer;    PAMAM;    Poly(amidoamine);    Ribonuclease;    Ribonuclease inhibitor;    Synergy;   

DOI  :  10.1016/j.bmcl.2010.11.028

来源: Elsevier

【 摘 要 】

Variants of bovine pancreatic ribonuclease (RNase A) engineered to evade the endogenous ribonuclease inhibitor protein (RI) are toxic to human cancer cells. Increasing the basicity of these variants facilitates their entry into the cytosol and thus increases their cytotoxicity. The installation of additional positive charge also has the deleterious consequence of decreasing ribonucleolytic activity or conformational stability. Here, we report that the same benefit can be availed by co-treating cells with a cationic dendrimer. We find that adding the generation 2 poly(amidoamine) dendrimer in trans increases the cytotoxicity of RI-evasive RNase A variants without decreasing their activity or stability. The increased cytotoxicity is not due to increased RI-evasion or cellular internalization, but likely results from improved translocation into the cytosol after endocytosis. These data indicate that co-treatment with highly cationic molecules could enhance the efficacy of ribonucleases as chemotherapeutic agents. (C) 2010 Elsevier Ltd. All rights reserved.

【 授权许可】

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