Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations that constitutively activate the phosphatidyl-inositol-3-kinase (PI3K) signaling pathway, including alterations in PI3K, PTEN, and AKT, are found in a variety of human cancers, implicating the PI3K lipid kinase as an attractive target for the development of therapeutic agents to treat cancer and other related diseases. In this study, we report on the combination of a novel organometallic kinase inhibitor scaffold with structure-based design to develop a PI3K inhibitor, called E5E2, with an IC 50 potency in the mid-low-nanomolar range and selectivity against a panel of protein kinases. We also show that E5E2 inhibits phospho-AKT in human melanoma cells and leads to growth inhibition. Consistent with a role for the PI3K pathway in tumor cell invasion, E5E2 treatment also inhibits the migration of melanoma cells in a 3D spheroid assay. The structure of the PI3Kgamma/E5E2 complex reveals the molecular features that give rise to this potency and selectivity toward lipid kinases with implications for the design of a subsequent generation of PI3K-isoform-specific organometallic inhibitors.
ACS Chem Biol 2008 May 16
PMID:Structure-based design of an organoruthenium phosphatidyl-inositol-3-kinase inhibitor reveals a switch governing lipid kinase potency and selectivity. 1848 10

Extracellular acidosis (low pH) is a tumor microenvironmental stressor that has a critical function in the malignant progression and metastatic dissemination of tumors. To survive under stress conditions, tumor cells must evolve resistance to stress-induced toxicity. Acyl-CoA synthetase 5 (ACSL5) is a member of the ACS family, which converts fatty acid to acyl-CoA. ACSL5 is frequently overexpressed in malignant glioma, whereas its functional significance is still unknown. Using retrovirus-mediated stable gene transfer (gain of function) and small interfering RNA-mediated gene silencing (loss of function), we show here that ACSL5 selectively promotes human glioma cell survival under extracellular acidosis. ACSL5 enhanced cell survival through its ACS catalytic activity. To clarify the genome-wide changes in cell signaling pathways by ACSL5, we performed cDNA microarray analysis and identified an ACSL5-dependent gene expression signature. The analysis revealed that ACSL5 was critical to the expression of tumor-related factors including midkine (MDK), a heparin-binding growth factor frequently overexpressed in cancer. Knockdown of MDK expression significantly attenuated ACSL5-mediated survival under acidic state. These results indicate that ACSL5 is a critical factor for survival of glioma cells under acidic tumor microenvironment, thus providing novel molecular basis for cancer therapy.
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PMID:Promotion of glioma cell survival by acyl-CoA synthetase 5 under extracellular acidosis conditions. 1880 31

By mimicking the phosphorylation of p19(INK4d), a tumor suppressor containing five ankyrin repeats, the native state could be destabilized to such an extent that only a partially folded state is populated at physiological temperature. This partly folded state, which mimics an on-pathway folding intermediate lacking structure in ankyrin repeats 1 and 2, is more rapidly ubiquitinated than the parent construct. Thus, phosphorylation of p19(INK4d) is likely to regulate cell-cycle progression through both biochemical (proteasomal) and biophysical (folding and binding to cyclin-dependent kinases) mechanisms.
ACS Chem Biol 2009 Jan 16
PMID:Biological regulation via ankyrin repeat folding. 1914 78

In this study, we describe optical detection of antibody-conjugated nanoparticles bound to surgically resected human pancreatic cancer tissue. Gold nanoparticles stabilized by heterobifunctional polyethylene glycol (PEG) were prepared using approximately 15 nm spherical gold cores and covalently coupled to F19 monoclonal antibodies. The heterobifunctional PEG ligands contain a dithiol group for stable anchoring onto the gold surface and a terminal carboxy group for coupling of antibodies to the outside of the PEG shell. The nanoparticle-antibody bioconjugates form highly stable dispersions and exhibit long-term resistance to agglomeration. This has been demonstrated by dynamic light scattering, size exclusion chromatography, and transmission electron microscopy. The nanoparticle bioconjugates were used to label tumor stroma in approximately 5 mum thick sections of resected human pancreatic adenocarcinoma. After rinsing away nonbound nanoparticles and fixation, the tissue samples were imaged by darkfield microscopy near the nanoparticle resonance scattering maximum (approximately 560 nm). The images display pronounced tissue features and suggest that this novel labeling method could provide for facile identification of cancer tissue. Tumor samples treated with gold nanoparticles conjugated to nonspecific control antibodies and noncancerous pancreatic tissue treated with mAb-F19-conjugated gold nanoparticles both exhibited correctly negative results and showed no tissue staining.
ACS Nano 2008 Nov 25
PMID:PEGylated gold nanoparticles conjugated to monoclonal F19 antibodies as targeted labeling agents for human pancreatic carcinoma tissue. 1920 92

The scaffold of nanoparticles (broadly defined as having a size range of 1-100 nm) presents a convenient platform to incorporate multiple functionalities into one single particle for cancer imaging and therapeutics. Whether hollow inside or not, a single nanoparticle can encapsulate a large payload of imaging probes, anticancer drug molecules, or both. On the surface, tumor-specific targeting molecules (e.g., receptor-binding ligands or antibodies) may be immobilized to facilitate active tumor targeting and drug delivery. This versatile nanoplatform promises more efficient delivery of payloads to tumors for improving cancer detection and treatment.
ACS Nano 2008 Oct 28
PMID:Shedding light on tumors using nanoparticles. 1920 54

Cisplatin (CDDP) was incorporated inside single-wall carbon nanohorns with holes opened (SWNHox) by a nanoprecipitation method that involved dispersion of CDDP and SWNHox in a solvent followed by the solvent evaporation. The incorporated CDDP quantity increased from the previously reported value of 15 to 46%, and the total released quantity of CDDP also increased from 60 to 100% by changing the solvent from dimethylformamide to water. Concurrently, in vitro anticancer efficiency of CDDP@SWNHox increased to 4-6 times greater than that of the intact CDDP. In vivo, CDDP@SWNHox intratumorally injected to transplanted tumors of mice suppressed the tumor growth more than the intact CDDP. We observed that CDDP@SWNHox adhered to the cell surfaces in vitro and stayed within the tumor tissues in vivo. Therefore, we think that the CDDP released from SWNHox realized high concentrations locally at the cells in vitro and in the tissues in vivo and could efficiently attack the tumor cells. We also found that SWNHox itself had an in vivo anticancer effect, which might increase the anticancer activities of CDDP@SWNHox.
ACS Nano 2008 Oct 28
PMID:Enhancement of in vivo anticancer effects of cisplatin by incorporation inside single-wall carbon nanohorns. 1920 52

We have developed a novel, reproducible, and facile methodology for the construction of artificial lipid envelopes for adenoviruses (Ad) by self-assembly of lipid molecules around the viral capsid. No alteration of the viral genome or conjugation surface chemistry at the virus capsid was necessary, therefore difficulties in production and purification associated with generating most surface-modified viruses can be eliminated. Different lipid bilayer compositions produced artificially enveloped Ad with physicochemical and biological characteristics determined by the type of lipid used. Physicochemical characteristics such as vector size, degree of aggregation, stability, and surface charge of the artificially enveloped Ad were correlated to their biological (gene transfer) function. In monolayer cell cultures, binding to the coxsackie and adenovirus receptor (CAR) was blocked using a zwitterionic envelope, whereas enhanced binding to the cell membrane was achieved using a cationic envelope. Envelopment of Ad by both zwitterionic and cationic lipid bilayers led to almost complete ablation of gene expression in cell monolayers, due to blockage of virion endosomal escape. Alternatively, artificial Ad envelopes built from lipid bilayers at the fluid phase in physiological conditions led to enhanced penetration of the vectors inside a three-dimensional tumor spheroid cell culture model and delayed gene expression in the tumor spheroid compared to nonenveloped adenovirus. These results indicate that construction of artificial envelopes for nonenveloped viruses by lipid bilayer wrapping of the viral capsids constitutes a general strategy to rationally engineer viruses at the nanoscale with control over their biological properties.
ACS Nano 2008 May
PMID:Nanoengineering artificial lipid envelopes around adenovirus by self-assembly. 1920 2

An amphiphilic tris(dibenzoylmethanato)europium(III) (Eu(DBM)(3)) coordinated P(MMA-co-EIPPMMA)-co-P(NIPAAm-co-NDAPM) copolymer was synthesized, which exhibited good biocompatibility and emitted strong red luminescence (MMA, methyl methacrylate; EIPPMMA, 4-(1-ethyl-1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)phenyl methacrylate; NIPAAm, N-isopropylacrylamide; NDAPM, (N-(3-dimethylamino)propyl)methacrylamide). The copolymer could self-assemble into micelles of size around 260 nm, and the micelles were thermosensitive at around body temperature. The drug-loaded micelles showed thermosensitive controlled drug release, and the paclitaxel loaded micelles were capable of being internalized into the tumor cells (A549) and exhibited obvious inhibition to the growth of A549 cells. Importantly, in vivo study showed the self-assembled micelles of Eu(DBM)(3) coordinated P(MMA-co-EIPPMMA)-co-P(NIPAAm-co-NDAPM) copolymer uptaken by the larvae of zebrafish could be easily tracked and be eliminated from the body within several days.
ACS Nano 2008 Jan
PMID:Cellular internalization and in vivo tracking of thermosensitive luminescent micelles based on luminescent lanthanide chelate. 1920 56

Heat shock protein 90 (Hsp90) is a promising cancer drug target, as multiple oncogenic proteins are destabilized simultaneously when it loses its activity in tumor cells. Highly selective Hsp90 inhibitors, including the natural antibiotics geldanamycin (GdA) and radicicol (RAD), inactivate this essential molecular chaperone by occupying its nucleotide binding site. Often cancer drug therapy is compromised by the development of resistance, but a resistance to these Hsp90 inhibitors should not arise readily by mutation of those amino acids within Hsp90 that facilitate inhibitor binding, as these are required for the essential ATP binding/ATPase steps of the chaperone cycle and are tightly conserved. Despite this, the Hsp90 of a RAD-producing fungus is shown to possess an unusually low binding affinity for RAD but not GdA. Within its nucleotide binding site a normally conserved leucine is replaced by isoleucine, though the chaperone ATPase activity is not severely affected. Inserted into the Hsp90 of yeast, this conservative leucine to isoleucine substitution recreated this lowered affinity for RAD in vitro. It also generated a substantially enhanced resistance to RAD in vivo. Co-crystal structures reveal that the change to isoleucine is associated with a localized increase in the hydration of an Hsp90-bound RAD but not GdA. To the best of our knowledge, this is the first demonstration that it is possible for Hsp90 inhibitor resistance to arise by subtle alteration to the structure of Hsp90 itself.
ACS Chem Biol 2009 Apr 17
PMID:Structural basis of the radicicol resistance displayed by a fungal hsp90. 1923 53

Carbon nanotube-based drug delivery holds great promise for cancer therapy. Herein we report the first targeted, in vivo killing of cancer cells using a drug-single wall carbon nanotube (SWNT) bioconjugate, and demonstrate efficacy superior to nontargeted bioconjugates. First line anticancer agent cisplatin and epidermal growth factor (EGF) were attached to SWNTs to specifically target squamous cancer, and the nontargeted control was SWNT-cisplatin without EGF. Initial in vitro imaging studies with head and neck squamous carcinoma cells (HNSCC) overexpressing EGF receptors (EGFR) using Qdot luminescence and confocal microscopy showed that SWNT-Qdot-EGF bioconjugates internalized rapidly into the cancer cells. Limited uptake occurred for control cells without EGF, and uptake was blocked by siRNA knockdown of EGFR in cancer cells, revealing the importance of EGF-EGFR binding. Three color, two-photon intravital video imaging in vivo showed that SWNT-Qdot-EGF injected into live mice was selectively taken up by HNSCC tumors, but SWNT-Qdot controls with no EGF were cleared from the tumor region in <20 min. HNSCC cells treated with SWNT-cisplatin-EGF were also killed selectively, while control systems that did not feature EGF-EGFR binding did not influence cell proliferation. Most significantly, regression of tumor growth was rapid in mice treated with targeted SWNT-cisplatin-EGF relative to nontargeted SWNT-cisplatin.
ACS Nano 2009 Feb 24
PMID:Targeted killing of cancer cells in vivo and in vitro with EGF-directed carbon nanotube-based drug delivery. 1923 65


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