Abstract
(1) Background: Natural peptides supporting the innate immune system studied at the functional and mechanistic level are a rich source of innovative compounds for application in human therapy. Increasing evidence indicates that apart from antimicrobial activity, some of them exhibit selective cytotoxicity towards tumor cells. Their cationic, amphipathic structure enables interactions with the negatively-charged membranes of microbial or malignant cells. It can be modeled in 3D by application of dendrimer chemistry. (2) Methods: Here we presented design principles, synthesis and bioactivity of branched peptides constructed from ornithine (Orn) assembled as proline (Pro)- or histidine (His)-rich dendrons and dendrimers of the bola structure. The impact of the structure and amphipathic properties of dendrons/dendrimers on two glioblastoma cell lines U87 and T98G was studied with the application of proliferation, apoptosis and cell migration assays. Cell morphology/cytoskeleton architecture was visualized by immunofluorescence microscopy. (3) Results: Dimerization of dendrons into bola dendrimers enhanced their bioactivity. Pro- and His-functionalized bola dendrimers displayed cytostatic activity, even though differences in the responsiveness of U87 and T98G cells to these compounds indicate that their bioactivity depends not only on multiple positive charge and amphipathic structure but also on cellular phenotype. (4) Conclusion: Ornithine dendrons/dendrimers represent a group of promising anti-tumor agents and the potential tools to study interrelations between drug bioactivity, its chemical properties and tumor cells’ phenotype.
Highlights
Numerous recent studies point to an increasing role of peptides as potential therapeutics for the treatment of a broad range of diseases
(2) Methods: Here we presented design principles, synthesis and bioactivity of branched peptides constructed from ornithine (Orn) assembled as proline (Pro)- or histidine (His)-rich dendrons and dendrimers of the bola structure
The impact of the structure and amphipathic properties of dendrons/dendrimers on two glioblastoma cell lines U87 and T98G was studied with the application of proliferation, apoptosis and cell migration assays
Summary
Numerous recent studies point to an increasing role of peptides as potential therapeutics for the treatment of a broad range of diseases. The application of cationic host defense peptides was rationalized for glioblastoma treatment by the studies of Riedl et al, who selectively targeted negatively charged phosphatidylserine molecules located on the external leaflet of the membranes [11] of melanoma, glioblastoma and a rhabdomyosarcoma cells as well as prostate and renal cancer cells by analogs of human Lactoferricin [12,13] Following these findings, efficacy of several structurally different AMP’s alone [14,15,16] or as hybrid materials [5,17,18,19,20] was tested against glioblastoma cells and showed their substantial activity along with structure-dependent versatility of mechanism of action [21,22,23]. Our data provide insight into the complexity of the determinants of dendrons/dendrimers bioactivity with the possible role of tumor-specific cell reactivity to these compounds
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