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. 2011 May 1;21(9):2756-8.
doi: 10.1016/j.bmcl.2010.11.028. Epub 2010 Nov 12.

Potentiation of Ribonuclease Cytotoxicity by a Poly(amidoamine) Dendrimer

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Free PMC article

Potentiation of Ribonuclease Cytotoxicity by a Poly(amidoamine) Dendrimer

Gregory A Ellis et al. Bioorg Med Chem Lett. .
Free PMC article

Abstract

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.

Figures

Figure 1
Figure 1
Electrostatic potential map of the RNase A surface with positively charged surface in blue, negatively charged surface in red, and neutral surface in white. Images were created with PDB entry 7rsa and the program PyMOL (DeLano Scientific, San Francisco, CA, USA).
Figure 2
Figure 2
Structure of the generation 2 poly(amidoamine) (PAMAM) dendrimer. The thirty amino nitrogens are in blue.
Figure 3
Figure 3
Effect of generation 2 PAMAM dendrimer on the inhibition of cancer cell proliferation by ribonucleases. The proliferation of K-562 cells was measured by the incorporation of [methyl-3H]thymidine. Data points represent the mean (± SE) of three separate experiments performed in triplicate.

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