discorhabdin-l and Prostatic-Neoplasms

Elements of the hypoxia inducible factor (HIF) transcriptional system, a key regulator of the cellular hypoxic response, are up-regulated in a range of cancer cells. HIF is fundamentally involved in tumor angiogenesis, invasion, and energy metabolism. Inhibition of the transcriptional activity of HIF may be of therapeutic benefit to cancer patients. We recently described the identification of two marine pyrroloiminoquinone alkaloids with potent activity in inhibiting the interaction between the oncogenic transcription factor HIF-1α and the coactivator protein p300. Herein, we present further characterization data for these two screening hits: discorhabdin H (

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Evaluation, Preclinical; E1A-Associated p300 Protein; Endothelial Cells; Gene Expression Regulation, Neoplastic; Heterocyclic Compounds, 4 or More Rings; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Mice; Mice, SCID; Neovascularization, Pathologic; Prostatic Neoplasms; Quinones; Rats; Signal Transduction

Inhibition of the hypoxia-inducible factor 1α (HIF-1α) pathway by disrupting its association with the transcriptional coactivator p300 inhibits angiogenesis and tumor development. Development of HIF-1α/p300 inhibitors has been hampered by preclinical toxicity; therefore, we aimed to identify novel HIF-1α/p300 inhibitors. Using a cell-free assay designed to test compounds that block HIF-1α/p300 binding, 170 298 crude natural product extracts and prefractionated samples were screened, identifying 25 active extracts. One of these extracts, originating from the marine sponge Latrunculia sp., afforded six pyrroloiminoquinone alkaloids that were identified as positive hits (IC50 values: 1-35 μM). Luciferase assays confirmed inhibition of HIF-1α transcriptional activity by discorhabdin B (1) and its dimer (2), 3-dihydrodiscorhabdin C (3), makaluvamine F (5), discorhabdin H (8), discorhabdin L (9), and discorhabdin W (11) in HCT 116 colon cancer cells (0.1-10 μM, p < 0.05). Except for 11, all of these compounds also reduced HIF-1α transcriptional activity in LNCaP prostate cancer cells (0.1-10 μM, p < 0.05). These effects occurred at noncytotoxic concentrations (<50% cell death) under hypoxic conditions. At the downstream HIF-1α target level, compound 8 (0.5 μM) significantly decreased VEGF secretion in LNCaP cells (p < 0.05). In COLO 205 colon cancer cells no activity was shown in the luciferase or cytotoxicity assays. Pyrroloiminoquinone alkaloids are a novel class of HIF-1α inhibitors, which interrupt the protein-protein interaction between HIF-1α and p300 and consequently reduce HIF-related transcription.

Topics: Alkaloids; Animals; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; E1A-Associated p300 Protein; HCT116 Cells; Heterocyclic Compounds, 4 or More Rings; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Marine Biology; Molecular Structure; Neovascularization, Pathologic; Porifera; Prostatic Neoplasms; Pyrroloiminoquinones; Quinones; Spiro Compounds; Thiazepines; Vascular Endothelial Growth Factor A