Potentiation of ribonuclease cytotoxicity by a poly(amidoamine) dendrimer

Ellis, Gregory A.; Hornung, Megan; Raines, Ronald T.

doi:10.1016/j.bmcl.2010.11.028

Cited by 6 publications

(6 citation statements)

References 36 publications

(39 reference statements)

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“…As expected, no effect on the viability of the cells was observed (Fig. [15][16][17][18][19][20] More recently, an alternative method has been developed to co-incubate RNase A with PAMAM dendrimers 58 but under the experimental conditions reported, only RNase A variants were successfully delivered. Aside from direct cytosolic injection, 9,10 most approaches to improve the efficiency of RNase A have involved the development of RI evasive mutant proteins.…”

Section: Cellular Uptake and Cytotoxicity Of Rnase Amentioning

confidence: 60%

Cationic poly(amidoamine) promotes cytosolic delivery of bovine RNase A in melanoma cells, while maintaining its cellular toxicity

Dubois

Lavignac

2015

J. Mater. Chem. B

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Ribonucleases are known to cleave ribonucleic acids, inducing cell death. RNase A, a member of the ribonuclease family, generally displayed poor in vitro activity. This has been attributed to factors such as low intracellular delivery. Poly(amidoamine)s have been used to promote the translocation of nonpermeant proteins to the cytosol. Our objective was to demonstrate that poly(amidoamine)s could potentially promote the delivery of RNase A to selected cell line. Interactions of three cationic poly(amidoamine)s (P1, P2 and ISA1) with wild-type bovine RNase A were investigated using gel retardation assays, DLS and microcalorimetry. Although the polymers and the protein are essentially cationic at physiological pH, complexation between the PAAs and RNase A was observed. The high sensitivity differential scanning calorimetry (HSDSC) thermograms demonstrated that the thermal stability of the protein was reduced when complexed with ISA1 (T max decreased by 6.5 1C) but was not affected by P1 and P2. All the polymers displayed low cytotoxicity towards non-cancerous cells (IC 50 4 3.5 mg mL À1 ). While RNase A alone was not toxic to mouse melanoma cells (B16F1), P1 was able to promote cytosolic delivery of biologically active RNase A, increasing cell death (IC 50 = 0.09 mg mL À1 ). † Electronic supplementary information (ESI) available: MP4 file for the 3D animation representing the surface of bovine RNase A (PDB: 1kf5) including the electrostatic potential and hydrophobic patches. See

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Section: Cellular Uptake and Cytotoxicity Of Rnase Amentioning

confidence: 60%

Cationic poly(amidoamine) promotes cytosolic delivery of bovine RNase A in melanoma cells, while maintaining its cellular toxicity

Dubois

Lavignac

2015

J. Mater. Chem. B

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“…Like for RI evasion, one has to be very cautious in the design of these variants in order to not counterbalance the increased internalization by the loss of other important characteristics responsible for the RNase cytotoxicity. In the same line but with a different approach, cotreating cells with a cationic 2 poly(amidoamine) dendrimer [144] increase the cytotoxicity of the RNase probably by increasing its translocation from the endosomes without affecting its ribonucleolytic activity or conformational stability observed upon cationization of some RNases.…”

Section: Engineered Rnases That Might Saturate the Intracellular Ri Amentioning

confidence: 99%

Approaches to Endow Ribonucleases with Antitumor Activity: Lessons Learned from the Native Cytotoxic Ribonucleases

Castro¹,

Ribó²,

Benito³

et al. 2016

Anti-Cancer Drugs - Nature, Synthesis and Cell

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Typical antitumor drugs disrupt the flow of biochemical information from DNA to proteins with the aim of precluding uncontrolled cell proliferation and inducing cancer cell apoptosis. However, most of the currently used small antitumor drugs are genotoxic because they act over DNA. Pharmaceutical industry is now searching for a new line of cancer chemotherapeutics without genotoxic effects. Ribonucleases (RNases) are small basic proteins, present in all life forms, which belong to this kind of chemotherapeutics. Some of them present with remarkable selective antitumor activity linked to their ability to destroy RNA, a powerful way to control gene expression, leaving DNA unharmed. In the last two decades, the knowledge gained on the cytotoxic mechanism of these RNases has been used to engineer more powerful and selective variants to kill cancer cells. In this chapter, we describe the advances reached in endowing an RNase with antitumor abilities.

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“…ptRNases can also be fused to cationic cell-penetrating peptides (CPPs) such as nonaarginine to increase internalization (Fuchs and Raines, 2005; Fuchs et al , 2007). These cationic moieties need not be appended to ptRNases, as the addition of a cationic poly(aminoamine) dendrimer in trans increases the internalization and cytotoxicity of a ptRNase (Ellis et al , 2011). We note, however, that increasing the positive charge of a ptRNase can have the adverse effect of increasing its affinity for RI, which is highly anionic (Johnson et al , 2007a).…”

Section: Attributes Of Cytotoxic Ptrnasesmentioning

confidence: 99%

Rational Design and Evaluation of Mammalian Ribonuclease Cytotoxins

Lomax

Eller

Raines

2012

Methods in Enzymology

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Mammalian pancreatic-type ribonucleases (ptRNases) comprise an enzyme family that is remarkably well suited for therapeutic exploitation. ptRNases are robust and prodigious catalysts of RNA cleavage that can naturally access the cytosol. Instilling cytotoxic activity requires endowing them with the ability to evade a cytosolic inhibitor protein while retaining other key attributes. These efforts have informed our understanding of ptRNase-based cytotoxins, as well as the action of protein-based drugs with cytosolic targets. Here, we address the most pressing problems encountered in the design of cytotoxic ptRNases, along with potential solutions. In addition, we describe assays that can be used to evaluate a successful design in vitro, in cellulo, and in vivo. The emerging information validates the continuing development of ptRNases as chemotherapeutic agents.

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Potentiation of ribonuclease cytotoxicity by a poly(amidoamine) dendrimer

Cited by 6 publications

References 36 publications

Cationic poly(amidoamine) promotes cytosolic delivery of bovine RNase A in melanoma cells, while maintaining its cellular toxicity

Cationic poly(amidoamine) promotes cytosolic delivery of bovine RNase A in melanoma cells, while maintaining its cellular toxicity

Approaches to Endow Ribonucleases with Antitumor Activity: Lessons Learned from the Native Cytotoxic Ribonucleases

Rational Design and Evaluation of Mammalian Ribonuclease Cytotoxins

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