The tumor suppressor, p53, plays an essential role in the cellular response to stress through regulating the expression of genes involved in cell cycle arrest, apoptosis and autophagy. Here, we used a cell-based reporter system for the detection of p53 response transcription to identify the marine sponge metabolites, ilimaquinone and ethylsmenoquinone, as activators of the p53 pathway. We demonstrated that ilimaquinone and ethylsmenoquinone efficiently stabilize the p53 protein through promotion of p53 phosphorylation at Ser15 in both HCT116 and RKO colon cancer cells. Moreover, both compounds upregulate the expression of p21WAF1/CIP1, a p53-dependent gene, and suppress proliferation of colon cancer cells. In addition, ilimaquinone and ethylsmenoquinone induced G2/M cell cycle arrest and increased caspase-3 cleavage and the population of cells that positively stained with Annexin V-FITC, both of which are typical biochemical markers of apoptosis. Furthermore, autophagy was elicited by both compounds, as indicated by microtubule-associated protein 1 light chain 3 (LC3) puncta formations and LC3-II turnover in HCT116 cells. Our findings suggest that ilimaquinone and ethylsmenoquinone exert their anti-cancer activity by activation of the p53 pathway and may have significant potential as chemo-preventive and therapeutic agents for human colon cancer.

High throughput screening of insulin secretion is intractable with current methods. We developed a secreted insulin-luciferase system (Ins-GLuc) in β cells that is rapid, inexpensive, and amenable to 96- and 384-well formats. We treated stable Ins-GLuc-expressing MIN6 cells overnight with 6298 marine natural product fractions. The cells were then washed to remove media and chemicals, followed by stimulation with glucose in the diazoxide paradigm. These conditions allowed the discovery of many insulin secretion suppressors and potentiators. The mechanisms of action of these natural products must be long-lasting given the continuance of secretory phenotypes in the absence of chemical treatment. We anticipate that these natural products and their target pathways will lead to a greater understanding of glucose-stimulated insulin secretion. Keywords: insulin, Gaussia, high-throughput screening, pancreatic islet beta cell, marine natural products.

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Colorectal cancer has emerged as a major cause of death in Western countries. Down-regulation of β-catenin expression has been considered a promising approach for cytotoxic drug formulation. Eight 4,9-friedodrimane-type sesquiterpenoids (1–8) were acquired using the oxidative potential of Verongula rigida on bioactive metabolites from two Smenospongia sponges. Compounds 3 and 4 contain a 2,2-dimethylbenzo[d]oxazol-6(2H)-one moiety as their substituted heterocyclic residues, which is unprecedented in such types of meroterpenoids. Gauge-invariant atomic orbital NMR chemical shift calculations were employed to investigate stereochemical details with support of the application of advanced statistics such as CP3 and DP4. Compounds 2 and 8 and the mixture of 3 and 4 suppressed β-catenin response transcription (CRT) via degrading β-catenin and exhibited cytotoxic activity on colon cancer cells, implying that their anti-CRT potential is, at least in part, one of their underlying antineoplastic mechanisms.

Activity-guided fractionation of a MeOH extract of the roots of Saussurea lappa C.B.Clarke (Compositae), using an in vitro protein tyrosine phosphatase 1B (PTP1B) inhibition assay, led to the isolation of four active constituents: betulinic acid (1), betulinic acid methyl ester (2), mokko lactone (3) and dehydrocostuslactone (4), along with nine inactive compounds. Our findings indicate that betulinic acid (1) and its methyl ester 2, as well as the two guaiane sesquiterpenoids 3 and 4 are potential lead moieties for the development of new PTP1B inhibitors.