(Thio)chromenone derivatives exhibit anti-metastatic effects through selective inhibition of uPAR in cancer cell lines: discovery of an uPAR-targeting fluorescent probe.

A class of (thio)chromenone derivatives has been identified as suitable ligands for uPAR, a glycoprotein with a prognostic value in a large number of human cancers. The (thio)chromenone agents actively inhibited the binding of uPAR to uPA with a binding affinity of 18.6 nM, reducing cell migration in the wound healing assay by up to 40% without apparent cell motility.

EGCG-induced selective death of cancer cells through autophagy-dependent regulation of the p62-mediated antioxidant survival pathway.

The effects of EGCG on the selective death of cancer cells by modulating antioxidant pathways through autophagy were explored in various normal and cancer cells. EGCG positively regulated the p62-KEAP1-NRF2-HO-1 pathway in normal cells, while negatively regulating it in cancer cells, leading to selective apoptotic death of cancer cells. In EGCG-treated MRC5 cells (EGCG-MRC5), autophagic flux was blocked, which was accompanied by the formation of p62-positive aggregates.

Transport Mechanism for Nuclear Localization of Irradiation-Activated EGFR Measured by Single-Molecule Pull-Down Assay.

Nuclear transport of epidermal growth factor receptor (EGFR) is considered to be a key cause of radiation resistance in cancer therapy. Here, we showed that irradiation-activated EGFR binds to the nuclear transport protein karyopherin alpha (KPNA) rather than karyopherin subunit beta 1 (KPNB1), through a single-molecule pull-down assay, which allows measurement of the binding affinity by single proteins in cell lysate without an additional purification step. We also obtained kinetic parameters for the binding between the phosphorylated nuclear localization signal (NLS) peptide of EGFR (RRRHIVRKRpTLRR) and KPNA.

Inhibition of NUPR1-Karyopherin β1 Binding Increases Anticancer Drug Sensitivity.

Background: Nuclear protein-1 (NUPR1, also known as p8/Com-1) is a transcription factor involved in the regulation of cellular stress responses, including serum starvation and drug stimulation.

Methods: We investigated the mechanism of NUPR1 nuclear translocation involving karyopherin β1 (KPNB1), using a single-molecule binding assay and confocal microscopy. The cellular effects associated with NUPR1-KPNB1 inhibition were investigated by gene expression profiling and cell cycle analysis.

HPLC and ToF‒SIMS Analyses of Tree Sap Mixed with Other Natural Lacquers.

Lacquer sap has been used by humans from antiquitywhen it was treated as a luxury item because of its desirable physical properties. In modern times, although access barriers are lower, lacquer is still considered to be rare and valuable. Thus, low quality, inexpensive Vietnamese and Myanmarese lacquers and cashew nutshell liquid are frequently added to the costly lacquer sap from Korea, China, and Japan.

Quantitative Analysis of Blended Asian Lacquers Using ToF-SIMS, Py-GC/MS and HPLC.

Asian lacquer is a special polymeric material tapped from lacquer trees. The tree's sap is a complex mixture of compounds, such as catechol lipids, polysaccharides, glycoproteins, enzymes, and water. Researchers have not yet quantitatively analyzed blended lacquers.

A Small Organic Molecule Blocks EGFR Transport into the Nucleus by the Nonclassical Pathway Resulting in Repression of Cancer Invasion.

In addition to the traditional epidermal growth factor receptor (EGFR) signaling pathways, nuclear EGFR has been shown to control multiple cellular functions, including cell proliferation and invasion. It has been reported that EGFR is transported into the nucleus after forming a complex with KPNA/KPNB1 or KPNB1. Herein, it is shown that EGFR can interact with both KP and KPNA, but EGF-activated EGFR mostly binds with KPNB1 through the pull-down assay.

Determination of the binding site of 2-aminothiazole derivative with importin β1 by UV-crosslinking experiment.

Importin β1 (KPBN1) appears to be overexpressed in several cancer cells and siRNA-induced inhibition of KPNB1 shows significant inhibition of cancer cell proliferation, but do not affect normal cells. These results indicate that KPNB1 is a potential target and inhibition of KPNB1 can be used as a novel therapeutic approach for the treatment of cancer. Recently, we identified the aminothiazole derivative 1 as a KPNB1-targeted anticancer agent.

Inhibition of Importin β1 With a 2-Aminothiazole Derivative Resulted in G/M Cell-cycle Arrest and Apoptosis.

Background: The design and synthesis of novel chemotherapeutic agents that can induce apoptosis and cell-cycle arrest has emerged as an attractive approach for the treatment of cancer, because they can limit possible nonspecific effects of compound treatment. Previous studies established that the expression of KPNB1 was increased in several cancer cells and transformed cell lines and inhibition of KPNB1 using siRNA significantly inhibited cervical tumour proliferation, but did not affect normal cervical epithelium. Recently, we reported that a KPNB1 inhibitor, the 2-aminothiazole derivative 1, possesses strong anti-proliferative effects against several cancer cells in the nanomolar concentration range.

Identification of KPNB1 as a Cellular Target of Aminothiazole Derivatives with Anticancer Activity.

We found that aminothiazole derivative (E)-N-(5-benzylthiazol-2-yl)-3-(furan-2-yl)acrylamide (1) has strong anticancer activity, and undertook proteomics approaches to identify the target protein of compound 1, importin β1 (KPNB1). A competitive binding assay using fluorescein-labeled 1 showed that 1 has strong binding affinity for KPNB1 (Kd : ∼20 nm). Furthermore, through western blotting assays for KPNB1, KPNA2, EGFR, ErbB2, and STAT3, we confirmed that 1 has inhibitory effects on the importin pathway.

Effect of oxygen plasma treatment on carbon nanotube-based sensors.

We present the research results of the use of plasma modification for the fabrication of carbon nanotube-based devices for chemical and biological sensing. The oxygen plasma treatment of multiwalled carbon nanotubes (MWCNTs) effectively grafts oxygen atoms onto the CNT surface. For investigating the impact of plasma modification on the MWCNT-based sensor performance, three different sensors are fabricated: NH3 gas sensors, humidity sensors, and immunosensors.

Selective death of cancer cells by preferential induction of reactive oxygen species in response to (-)-epigallocatechin-3-gallate.

(-)-Epigallocatechin-3-gallate (EGCG) induces apoptosis in cancer cells without adversely affecting normal cells. Understanding the cancer-specific cytotoxic activity of EGCG is very important in defining the mechanism of tumorigenesis and identifying superb chemotherapeutic agents against cancer. We comparatively assayed human telomerase reverse transcriptase (hTERT)-mediated apoptosis by EGCG-induced reactive oxygen species (ROS) in normal cells and cancer cells.

Novel thiazolidinedione derivatives with anti-obesity effects: dual action as PTP1B inhibitors and PPAR-γ activators.

Benzylidene-2,4-thiazolidinedione derivatives with substitutions at both the ortho and para-positions of the phenyl group were synthesized as PTP1B inhibitors with IC(50) values in a low micromolar range. Compound 18l, the lowest, bore an IC(50) of 1.3 μM.

A novel organogermanium protected atopic dermatitis induced by oxazolone.

Atopic dermatitis (AD) is a chronic inflammatory disease of the skin that is often associated with other atopic diseases, such as asthma and allergic rhinitis. Although topical steroids have widely been prescribed for patients with AD, skin abnormalities are frequently observed after prolonged steroid treatment. In this study, a novel water-soluble organogermanium compound (Ge-Vit) was prepared because organogermanium is a known INF-gamma inducer.

Synthesis and biological evaluation of water-soluble organogermanium.

Interferon (INF) is an effective drug in treating several human diseases. Ge-132, which is the most common and well-studied organic germanium, has been reported to induce INF-gamma and has undergone clinical trials with promising preclinical results. However, it has been reported that long-term ingestion or high doses of organic Ge-132 causes similar toxic effects as GeO(2) because Ge-132 can be easily contaminated with significant amounts of inorganic germanium during the preparation.

TSA-induced DNMT1 down-regulation represses hTERT expression via recruiting CTCF into demethylated core promoter region of hTERT in HCT116.

Trichostatin A (TSA), an inhibitor of histone deacetylase, is a well-known antitumor agent that effectively and selectively induces tumor growth arrest and apoptosis. Recently, it was reported that hTERT is one of the primary targets for TSA-induced apoptosis in cancer cells but the mechanism of which has not yet been elucidated. In the present study, to better understand the epigenetic regulation mechanism responsible for the repression of hTERT by TSA, we examined expression of hTERT in the HCT116 colon cancer cell line after treatment with TSA and performed site-specific CpG methylation analysis of the hTERT promoter.

Thiazolidinedione derivatives as PTP1B inhibitors with antihyperglycemic and antiobesity effects.

Benzylidene-2,4-thiazolidinedione derivatives with substitutions on the phenyl ring at the ortho or para positions of the thiazolidinedione (TZD) group were synthesized as PTP1B inhibitors with IC50 values in a low micromolar range. Compound 3e, the lowest, bore an IC50 of 5.0 microM.

Structure-based virtual screening approach to identify novel classes of Cdc25B phosphatase inhibitors.

Discovery of Cdc25B phosphatase inhibitors has been actively pursued with the aim to develop anticancer agents. We have been able to identify eight novel Cdc25B inhibitors by means of a computer-aided drug design protocol involving the virtual screening with docking simulations under consideration of the effects of ligand solvation in the binding free energy function. Structural features relevant to the interactions of the newly identified inhibitors with the active-site residues of Cdc25B are also discussed in detail.

Structure-based virtual screening approach to identify novel classes of PTP1B inhibitors.

Discovery of protein tyrosine phosphatase 1B (PTP1B) inhibitors has been actively pursued with the aim to develop therapeutics for the treatment of type 2 diabetes and obesity. We have been able to identify 9 novel PTP1B inhibitors by means of a computer-aided drug design protocol involving virtual screening with docking simulations under consideration of the effects of ligand solvation in the binding free energy function. Because the newly discovered inhibitors are structurally diverse and reveal a significant potency with IC(50) values lower than 50 microM, all of them can be considered for further development by structure-activity relationship studies.

2-O-carboxymethylpyrogallol derivatives as PTP1B inhibitors with antihyperglycemic activity.

2-O-carboxymethylpyrogallol derivatives (4-17) were synthesized, with their in vitro inhibitory activities against PTP1B and in vivo antihyperglycemic effects examined. Compound 14, the most potent among the series, showed a K(i) value of 1.1 microM against PTP1B, 7-fold lower than that against TC-PTP.

Fluorinated NSC as a Cdc25 inhibitor.

We report on the fluorinated form of NSC 95397 as a Cdc25B inhibitor, which is predicted to be only an arylator of cysteine-containing proteins, without generating reactive oxygen species.

H32, a non-quinone sulfone analog of vitamin K3, inhibits human hepatoma cell growth by inhibiting Cdc25 and activating ERK.

We previously synthesized a K-vitamin derivative, Cpd 5, which was a potent growth inhibitor of human tumor cells, including Hep3B hepatoma cells. However, being a quinone compound, Cpd 5 has the potential for generating toxic reactive oxygen species (ROS). We therefore synthesized a nonquinone sulfone derivative, H32, which has a sufone group substituting the quinone.

Fluorinated Cpd 5, a pure arylating K-vitamin derivative, inhibits human hepatoma cell growth by inhibiting Cdc25 and activating MAPK.

We previously synthesized several K-vitamin derivatives, which are potent growth inhibitors of human tumor cells, including Hep3B human hepatoma cells. Among these, Cpd 5 was the most potent. However, being a quinone derivative, Cpd 5 has the potential for generating toxic reactive oxygen species (ROS).

Novel hydroxyl naphthoquinones with potent Cdc25 antagonizing and growth inhibitory properties.

Cdc25 phosphatases are important in cell cycle control and activate cyclin-dependent kinases (Cdk). Efforts are currently under way to synthesize specific small-molecule Cdc25 inhibitors that might have anticancer properties. NSC 95397, a protein tyrosine phosphatase antagonist from the National Cancer Institute library, was reported to be a potent Cdc25 inhibitor.

Fluorinated quinoid inhibitor: possible "pure" arylator predicted by the simple theoretical calculation.

We report on the fluorinated form of Cpd 5 as a cell growth inhibitor. This compound is 3-fold more potent than the parent Cpd 5 and is predicted, using the semi-empirical AM1 method to be only an arylator of cysteine-containing proteins, without generating reactive oxygen species.