ABSTRACT
Advances in mechanistic understanding of integrin-mediated adhesion highlight the importance of precise control of ligand presentation in directing cell migration. Top-down nanopatterning limited the spatial presentation to sub-micron placing restrictions on both fundamental study and biomedical applications. To break the constraint, here we propose a bottom-up nanofabrication strategy to enhance the spatial resolution to the molecular level using simple formulation that is applicable as treatment agent. Via self-assembly and co-assembly, precise control of ligand presentation is succeeded by varying the proportions of assembling ligand and nonfunctional peptide. Assembled nanofilaments fulfill multi-functions exerting enhancement to suppression effect on cell migration with tunable amplitudes. Self-assembled nanofilaments possessing by far the highest ligand density prevent integrin/actin disassembly at cell rear, which expands the perspective of ligand-density-dependent-modulation, revealing valuable inputs to therapeutic innovations in tumor metastasis.
Subject(s)
Integrins , Cell Adhesion/physiology , Cell Movement/physiology , Integrins/metabolism , Ligands , Protein BindingABSTRACT
Two new steroid sulfates 1 and 2 were obtained from a lipophilic extract of an undescribed bryozoan species in the genus Calyptotheca. The structures of compounds 1 and 2 were elucidated by spectroscopic methods and chemical modifications. Steroids 1 and 2 exhibited moderate cytotoxicity at IC50 54 and 30 µM, respectively, against NBT-T2 cells.
Subject(s)
Bryozoa , Sulfates , Animals , SteroidsABSTRACT
Heparan sulfate (HS) has important emerging roles in oncogenesis, which represents potential therapeutic strategies for human cancers. However, due to the complexity of the HS signaling network, HS-targeted synthetic cancer therapeutics has never been successfully devised. To conquer the challenge, we developed HS-instructed self-assembling peptides by decorating the "Cardin-Weintraub" sequence with aromatic amino acids. The HS-binding interactions induce localized accumulation of synthetic peptides triggering molecular self-assembly in the vicinity of highly expressed Heparan sulfate proteoglycans (HSPGs) on the cancer cell membrane. The nanostructures hinder the binding of HSPG with metastasis promoting protein-heparin-binding EGF-like growth factor (HBEGF) inhibiting the activation of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK). Our study proved that HS-instructed self-assembly is a promising synthetic therapeutic strategy for targeted cancer migration inhibition.
Subject(s)
Cell Movement/drug effects , Heparitin Sulfate/chemistry , Heparitin Sulfate/pharmacology , Cell Line, Tumor , Extracellular Signal-Regulated MAP Kinases/metabolism , Humans , Nanostructures/chemistry , Neoplasm MetastasisABSTRACT
The Yes-associated protein (YAP) is a major oncoprotein responsible for cell proliferation control. YAP's oncogenic activity is regulated by both the Hippo kinase cascade and uniquely by a mechanical-force-induced actin remodeling process. Inspired by reports that ovarian cancer cells specifically accumulate the phosphatase protein ALPP on lipid rafts that physically link to actin cytoskeleton, we developed a molecular self-assembly (MSA) technology that selectively halts cancer cell proliferation by inactivating YAP. We designed a ruthenium-complex-peptide precursor molecule that, upon cleavage of phosphate groups, undergoes self-assembly to form nanostructures specifically on lipid rafts of ovarian cancer cells. The MSAs exert potent, cancer-cell-specific antiproliferative effects in multiple cancer cell lines and in mouse xenograft tumor models. Our work illustrates how basic biochemical insights can be exploited as the basis for a nanobiointerface fabrication technology which links nanoscale protein activities at specific subcellular locations to molecular biological activities to suppress cancer cell proliferation.
Subject(s)
Ovarian Neoplasms , Protein Serine-Threonine Kinases , Actins , Animals , Female , Humans , Membrane Microdomains , Mice , Ovarian Neoplasms/drug therapy , Protein Serine-Threonine Kinases/metabolism , Signal TransductionABSTRACT
Metastasis is one of the ongoing challenges in cancer therapy which most treatments failed to address. Inspired by the upregulated expression of both integrin ß1 and heparan sulfate in metastatic tumors, we developed an integrin/HS dual-targeting peptide assembly that selectively inhibits cancer cell migration and invasion. Particularly, the dual-targeting peptide self-assembles into nanofibrous microdomains specifically on the cancer cell membrane, triggering spatial organization of integrins, which form clusters on the apical membrane. Via the actin cytoskeleton that physically connects to integrin clusters, the oncogene yes-associated protein, which regulates cancer metastasis, is deactivated. We showed that in multiple cancer cell lines, including the highly metastatic pancreatic cancer cells, the dual-targeting peptide exerts potent and dose-dependent antimetastatic effects. Our work illustrates how basic biochemical insights can be exploited as the basis for nano-biointerface fabrication, which is potentially a general design strategy for nanomedicine development.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Movement/drug effects , Heparitin Sulfate/metabolism , Integrin beta1/metabolism , Peptides/pharmacology , Adaptor Proteins, Signal Transducing/metabolism , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Drug Design , Humans , Peptides/chemical synthesis , Transcription Factors/metabolism , YAP-Signaling ProteinsABSTRACT
Malignant brain cancer remains challenging in treatment due to the highly invasive quality of gliomas. Inspired by the upregulated expression of integrin ß1 subunits in tumors, we designed and synthesized an integrin-targeting self-assembling ligand based on a laminin-derived peptide that selectively forms nanofibrous microdomains on the apical membrane of glioma cells, inhibiting their migration and invasion.
Subject(s)
Glioma , Cell Movement , Glioma/drug therapy , Humans , Integrin beta1 , Integrins , LigandsABSTRACT
Three new cembranolides (1-3) were isolated from an Okinawan soft coral, Lobophytum sp., together with the known cembranolide diterpenoids (4-9). Their structures were determined by extensive analysis of spectroscopic data (1D and 2D NMR, IR, and MS), molecular modeling, and comparison with data reported elsewhere. All compounds contain an α-methylene-γ-lactone ring adjacent to a cembrane, and some of them (1, 6-8) have an epoxide ring as well. The new metabolites were evaluated for cytotoxicity against HeLa, A459, B16-F10, and RAW 264.7 cells and anti-inflammatory effect in LPS-stimulated inflammatory RAW 264.7 macrophage cells.
Subject(s)
Anthozoa/chemistry , Diterpenes/pharmacology , Animals , Diterpenes/isolation & purification , HeLa Cells , Humans , Japan , Melanoma, Experimental , Mice , Molecular Structure , RAW 264.7 CellsABSTRACT
Inspired by the metamorphosis of pore-forming toxins from soluble inactive monomers to cytolytic transmembrane assemblies, we developed self-assembly-directed membrane insertion of synthetic analogues for permeability alteration. An expanded π-conjugation-based molecular precursor with an extremely high rigidity and a long hydrophobic length that is comparable to the hydrophobic width of plasma membrane was synthesized for membrane-inserted self-assembly. Guided by the cancer biomarker expression in vitro, the soluble precursors transform into hydrophobic monomers forming assemblies inserted into the fluid phase of the membrane exclusively. Membrane insertion of rigid synthetic analogues destroys the selective permeability of the plasma membrane gradually. It eventually leads to cancer cell death, including drug resistant cancer cells.
Subject(s)
Cell Membrane Permeability , HeLa Cells , Humans , Hydrophobic and Hydrophilic Interactions , Molecular Conformation , Molecular Dynamics Simulation , Toxins, Biological/chemistry , Toxins, Biological/metabolismABSTRACT
The precision and efficacy of photodynamic therapy (PDT) is essential for the treatment of brain tumors because the cancer cells are within or adjacent to the delicate nervous system. Taurine is an abundant amino acid in the brain that serves the central nervous system (CNS). A taurine-modified polypyridyl Ru-complex was shown to have optimized intracellular affinity in cancer cells through accumulation in lysosomes. Symmetrical modification of this Ru-complex by multiple taurine molecules enhanced the efficiency of molecular emission with boosted generation of reactive oxygen species. These characteristic features make the taurine-modified Ru-complex a potentially effective photosensitizer for PDT of target cancer cells, with outstanding efficacy in cancerous brain cells.
Subject(s)
Antineoplastic Agents/pharmacology , Brain Neoplasms/drug therapy , Photochemotherapy , Photosensitizing Agents/pharmacology , Ruthenium/pharmacology , Taurine/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Cell Death/drug effects , Cell Line , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Screening Assays, Antitumor , Humans , Molecular Conformation , PC12 Cells , Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/chemistry , Rats , Reactive Oxygen Species/metabolism , Ruthenium/chemistry , Taurine/chemistryABSTRACT
The helicase portion of the hepatitis C virus nonstructural protein 3 (NS3) is considered one of the most validated targets for developing direct acting antiviral agents. We isolated polybrominated diphenyl ether (PBDE) 1 from a marine sponge as an NS3 helicase inhibitor. In this study, we evaluated the inhibitory effects of PBDE (1) on the essential activities of NS3 protein such as RNA helicase, ATPase, and RNA binding activities. The structure-activity relationship analysis of PBDE (1) against the HCV ATPase revealed that the biphenyl ring, bromine, and phenolic hydroxyl group on the benzene backbone might be a basic scaffold for the inhibitory potency.
