Activation of insulin-like growth factor receptor signaling mediates resistance to histone deacetylase inhibitors.

Histone deacetylases (HDACs) are considered promising targets in the treatment of hematologic malignancies and several types of solid tumors, including non-small cell lung cancer (NSCLC). However, the efficacy of HDAC inhibitors in solid tumors is marginal, and the mechanisms underlying resistance to HDAC inhibitors are largely unknown. Here, we demonstrate the involvement of type 1 insulin-like growth factor receptor (IGF-1R) signaling in resistance to HDAC inhibitors in NSCLC.

Silencing gastrin-releasing peptide receptor suppresses key regulators of aerobic glycolysis in neuroblastoma cells.

Background: Under normoxic conditions, cancer cells use aerobic glycolysis as opposed to glucose oxidation for energy production; this altered metabolism correlates with poor outcomes in neuroblastoma. Hypoxia-inducible factor-1 alpha (HIF-1α) and pyruvate dehydrogenase kinase 4 (PDK4) regulate aerobic glycolysis, while pyruvate dehydrogenase phosphatase 2 (PDP2) promotes glucose oxidation. Here, we sought to determine whether gastrin-releasing peptide receptor (GRP-R) signaling regulates glucose metabolism.

Combating resistance to anti-IGFR antibody by targeting the integrin β3-Src pathway.

Background: Several phase II/III trials of anti-insulin-like growth factor 1 receptor (IGF-1R) monoclonal antibodies (mAbs) have shown limited efficacy. The mechanisms of resistance to IGF-1R mAb-based therapies and clinically applicable strategies for overcoming drug resistance are still undefined.

Methods: IGF-1R mAb cixutumumab efficacy, alone or in combination with Src inhibitors, was evaluated in 10 human head and neck squamous cell carcinoma (HNSCC) and six non-small cell lung cancer (NSCLC) cell lines in vitro in two- or three-dimensional culture systems and in vivo in cell line- or patient-derived xenograft tumors in athymic nude mice (n = 6-9 per group).

Antitumor effects of dietary black and brown rice brans in tumor-bearing mice: relationship to composition.

Scope: Feeding a diet supplemented with 10% (w/w) black and brown rice brans inhibited growth of transplanted tumors in mice.

Methods And Results: Black and brown rice brans from Oryza sativa LK1-3-6-12-1 and Chuchung cultivars each contained 21 compounds characterized by GC/MS. Mice fed diets with added rice brans for 2 weeks were intracutaneously inoculated with CT-26 mouse cancer cells and fed the same diet for two additional weeks.

Hedgehog-mediated regulation of PPARγ controls metabolic patterns in neural precursors and shh-driven medulloblastoma.

Sonic hedgehog (Shh) signaling is critical during development and its aberration is common across the spectrum of human malignancies. In the cerebellum, excessive activity of the Shh signaling pathway is associated with the devastating pediatric brain tumor medulloblastoma. We previously demonstrated that exaggerated de novo lipid synthesis is a hallmark of Shh-driven medulloblastoma and that hedgehog signaling inactivates the Rb/E2F tumor suppressor complex to promote lipogenesis.

Protective effects of black rice bran against chemically-induced inflammation of mouse skin.

We investigated the inhibitory effects of black rice (cv. LK1-3-6-12-1-1) bran against 12-O-tetradecanolylphorbol-13-acetate (TPA)-induced skin edema and 2,4-dinitrofluorobenzene (DNFB)-induced allergic contact dermatitis (ACD) in inflammatory mouse models. We also determined the effects of the bran extract on the following biomarkers: pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), eicosanoids leukotriene B4 (LTB4), and prostaglandin E2 (PGE2).

Antiallergic activities of pigmented rice bran extracts in cell assays.

Using a panel of chemical, biochemical, and cell assays, we determined inhibitory effects of extracts of the pigmented black rice brans on in vitro allergic reactions. Ethanol-water (70% v/v) extracts from 5 pigmented brans were found to be more effective than an extract from a nonpigmented rice cultivar in suppressing the release of histamine and beta-hexosaminidase from basophilic RBL-2H3 cells stimulated with both Ionophore A23187 and immunoglobulin E (IgE)-antigen complexes. Suppression was also obtained with A23187-stimulated rat peritoneal mast cells.

Antioxidative, antimutagenic, and anticarcinogenic activities of rice bran extracts in chemical and cell assays.

Ethanol-water (70:30 v/v) extracts from rice brans removed from seeds of two blackish-purple pigmented (Sanhaehyanghyulla and Suwon 415) and one nonpigmented (Chuchung) brown rice cultivars were evaluated for antioxidative, anti-tumor-promoting, and anticarcinogenic activities in chemical assays and in mammalian cells (human leukemia HL-60, marmoset B lymphoblastoid B95-8, and Chinese hamster V79 lung cells) by the following tests: inhibition of xanthine oxidase activity; chelation of ferrous ions; reduction of potassium ferricyanide; scavenging of superoxide anions, hydroxyl radicals, and intracellular peroxides; inhibition of 4-nitroquinoline N-oxide-induced mutagenesis; and inhibition of phorbol ester-induced tumor promotion. The extracts from the pigmented rice seeds had generally higher activities in all tests than did the extract from the nonpigmented variety. The results suggest that brans from pigmented rice varieties may provide a source of new natural antioxidants and anticarcinogens and that such rice cultivars with high antioxidative potential also provide a genetic resource for the development of new, improved rice cultivars that may make it possible to enhance both the nutritional and medical value of rice-based diets.

Constitutive expression of 4-1BB on T cells enhances CD4+ T cell responses.

4-1BB, a transmembrane molecule, member of the tumor necrosis factor receptor superfamily, is an important costimulatory molecule in the immune response, plays a key role in the clonal expansion and survival of CD8(+) T cells. In this study, we investigated 4-1BB regulation of CD4(+) T cell responses using 4-1BB transgenic (TG) mice that constitutively expressed 4-1BB on mature T cells. We first showed that CD4(+) T cells of 4-1BB TG mice had more sustained proliferative capacity in response to TCR/4-1BB stimulation in vitro compared to WT mice.