Natural product drug discovery efforts rely on libraries of organisms to provide access to diverse pools of compounds. Actionable strategies to rationally maximize chemical diversity, rather than relying on serendipity, can add value to such efforts.
A screening program designed to identify natural products with selective cytotoxic effects against cell lines representing different types of pediatric solid tumors led to the identification of altertoxin II as a highly potent and selective cytotoxin against Ewing sarcoma cell lines. Altertoxin II, but not the related compounds altertoxin I and alteichin, was highly effective against every Ewing sarcoma cell line tested, with an average 25-fold selectivity for these cells as compared to cells representing other pediatric and adult cancers. Mechanism of action studies revealed that altertoxin II causes DNA double-strand breaks, a rapid DNA damage response, and cell cycle accumulation in the S phase. Our studies also demonstrate that the potent effects of altertoxin II are partially dependent on the progression through the cell cycle, because the G1 arrest initiated by a CDK4/6 inhibitor decreased antiproliferative potency more than 10 times. Importantly, the cell-type-selective DNA-damaging effects of altertoxin II in Ewing sarcoma cells occur independently of its ability to bind directly to DNA. Ultimately, we found that altertoxin II has a dose-dependent in vivo antitumor efficacy against a Ewing sarcoma xenograft, suggesting that it has potential as a therapeutic drug lead and will be useful to identify novel targets for Ewing-sarcoma-specific therapies.
ADDITIONAL INDEX WORDS. alternative container, green industry, landscape performance, sustainability SUMMARY. As the green industry is moving toward sustainability to meet the demands of society, the use of biocontainers as alternatives to petroleum-based plastic containers has drawn significant attention. Field trials of seven plantable biocontainers (coir, manure, peat, rice hull, soil wrap, straw, and wood fiber) were conducted in 2011 and 2012 at five locations in the United States to assess the influence of direct-plant biocontainers on plant growth and establishment and the rate of container decomposition in landscape. In 2011, container type did not affect the growth of any of the three species used in this study with an exception in one location. The three species were 'Sunpatiens Compact Magenta' new guinea impatiens (Impatiens ·hybrida), 'Luscious Citrus' lantana (Lantana camara), and 'Senorita Rosalita' cleome (Cleome ·hybrida). In 2012, the effect of container type on plant growth varied with location and species. Cleome, new guinea impatiens, and lantana plants grown in coir and straw containers were in general smaller than those in peat, plastic, rice hull, and wood fiber containers. After 3 to 4 months in the field, manure containers had on average the highest rate of decomposition at 88% for all five locations and two growing seasons. The levels of decomposition of other containers, straw, wood fiber, soil wrap, peat, coir, and rice hull were 47%, 46%, 42%, 38%, 25%, and 18%, respectively, in descending order. Plantable containers did not hinder plant establishment and posttransplant plant growth. The impact of container type on plant growth was smaller compared with that of location (climate). Similarly, the impact of plant species on pot decomposition was smaller compared with that of pot material.
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