Sunday, July 24, 2011

Novel compound selectively kills cancer cells

A cancer cell may seem out of control, growing wildly and breaking all the rules of orderly cell life and death. But amid the seeming chaos there is a balance between a cancer cell's revved-up metabolism and skyrocketing levels of cellular stress. Just as a cancer cell depends on a hyperactive metabolism to fuel its rapid growth, it also depends on anti-oxidative enzymes to quench potentially toxic reactive oxygen species (ROS) generated by such high metabolic demand.

Scientists at the Broad Institute and Massachusetts General Hospital (MGH) have discovered a novel compound that blocks this response to oxidative stress selectively in but spares normal cells, with an effectiveness that surpassed a chemotherapy drug currently used to treat breast cancer. Their findings, based on experiments in cell culture and in mice, appear online in Nature on July 13.

The plant-based compound piperlongumine (PL), derived from the fruit of a pepper plant found in southern India and southeast Asia, appears to kill cancer cells by jamming the machinery that dissipates high oxidative stress and the resulting ROS. Normal cells have low levels of ROS, in tune with their more modest metabolism, so they don't need high levels of the anti-oxidant enzymes that PL stymies once they pass a certain threshold.

"Piperlongumine targets something that's not thought to be essential in normal cells," said Stuart L. Schreiber, a senior co-author and director of the Broad's Chemical Biology Program. "Cancer cells have a greater dependence on ROS biology than normal cells."

Sam W. Lee and Anna Mandinova, senior co-authors from the Cutaneous Biology Research Center (CBRC) at MGH, weren't looking for a ROS inhibitor when they found PL. Their interest lay in the tumor suppressor , which is mutated in more than half of all . Teaming up with the Broad's Chemical Biology Program and Platform to screen libraries of , they were looking for something that might increase levels of the properly functioning p53 gene.

When they saw a promising signal for PL, they assumed it worked by enhancing the p53 gene. But to their surprise, PL induced cancer cell death independent of the tumor suppressor gene's activity. And when they tested PL in normal cells, the cells didn't die.

"The novelty of this compound was that it was able to recognize cancer cells from normal cells," said Mandinova, a Broad associate member and a faculty member at MGH and Harvard Medical School. "It has a mode of action that targets something especially important to the cancer cell."

Their second surprise came after the Proteomics Platform's quantitative analysis identified the target of PL. The researchers imagined that they might find a protein encoded by a cancer-causing gene was being inhibited in some way, but instead of an oncogene, they saw an indirect process on which cancer cells depend.

A small number of new cancer drugs target oncogenes directly, but this may not be the only promising new direction for treating cancers. Cancer genes do not act alone. PL exploits a dependency that develops after oncogenes transform normal cells into cancer cells.

"Our studies suggest that piperlongumine's ROS-associated mechanism is especially relevant to the transformed cancer cell," said co-author Andrew M. Stern, associate director of Novel Therapeutics at the Broad. "And this in part may underlie the observed selectivity of PL."

The scientists tested PL against cancer cells and normal cells engineered to develop cancer. In mice injected with human bladder, breast, lung, or melanoma cancer cells, PL inhibited tumor growth but showed no toxicity in normal mice. In a tougher test of mice that developed spontaneously, PL blocked both tumor growth and metastasis. In contrast, the chemotherapy drug paclitaxel (Taxol) was less effective, even at high levels.

"This compound is selectively reducing the enzyme activity involved in oxidative stress balance in cancer cells, so the ROS level can go up above the threshold for cell death," said Lee, a Broad associate member and associate director of CBRC at MGH. "We hope we can use this compound as a starting point for the development of a drug so patients can benefit."

While hopeful, the authors remain cautious. Much more work needs to be done to better understand how the ROS process differs between normal and cancer cells before clinical studies can even be launched. Further studies will focus on different forms of cancer and their genotypes, or genetic information.

"Our next set of goals is to learn if there are specific cancer genotypes that will be more sensitive to this compound than others," said Alykhan F. Shamji, associate director of the Broad's Chemical Biology Program. "We hope our experiments will help be predictive of whether patients with the same genotypes in their tumors would respond the same way. It would help us to pick the right patients."

More information: Raj L et al. Selective killing of cancer cells with a small molecule targeting stress response to ROS. Nature. Published online July 13, 2011. DOI: 10.1038/nature10167

Provided by Massachusetts Institute of Technology (news : web)

Dry onion skin has a use

More than 500,000 tonnes of onion waste are thrown away in the European Union each year. However, scientists say this could have a use as food ingredients. The brown skin and external layers are rich in fibre and flavonoids, while the discarded bulbs contain sulphurous compounds and fructans. All of these substances are beneficial to health.

Production of onion waste has risen over recent years in line with the growing demand for these bulbs. More than 500,000 tonnes of waste are generated in the European Union each year, above all in Spain, Holland and the United Kingdom, where it has become an environmental problem. The waste includes the dry brown skin, the outer layers, roots and stalks, as well as onions that are not big enough to be of commercial use, or onions that are damaged.

"One solution could be to use onion waste as a natural source of ingredients with high functional value, because this vegetable is rich in compounds that provide benefits for human health", Vanesa Benítez, a researcher at the Department of Agricultural Chemistry at the Autonomous University of Madrid (Spain), tells SINC.

Benítez's research group worked with scientists from Cranfield University (United Kingdom) to carry out laboratory experiments to identify the substances and possible uses of each part of the onion. The results have been published in the journal Plant Foods for Human Nutrition.

According to the study, the brown skin could be used as a functional ingredient high in dietary fibre (principally the non-soluble type) and phenolic compounds, such as quercetin and other flavonoids (plant metabolites with medicinal properties). The two outer fleshy layers of the onion also contain fibre and flavonoids.

"Eating fibre reduces the risk of suffering from cardiovascular disease, gastrointestinal complaints, colon cancer, type-2 diabetes and obesity", the researcher points out.

Phenolic compounds, meanwhile, help to prevent coronary disease and have anti-carcinogenic properties. The high levels of these compounds in the dry skin and the outer layers of the bulbs also give them high antioxidant capacity.

Meanwhile, the researchers suggest using the internal parts and whole onions that are thrown away as a source of fructans and sulphurous compounds. Fructans are prebiotics, in other words they have beneficial health effects as they selectively stimulate the growth and activity of bacteria in the colon.

Sulphurous compounds reduce the accumulation of platelets, improving blood flow and cardiovascular health in general. They also have a positive effect on antioxidant and anti-inflammatory systems in mammals.

"The results show that it would be useful to separate the different parts of onions produced during the industrial process", explains Benítez. "This would enable them to be used as a source of functional compounds to be added to other foodstuffs".

Original publication:
V. Benítez, E. Mollá, M. A. Martín-Cabrejas, Y. Aguilera, F. J. López-Andréu, K. Cools, L. A. Terry, R. M. Esteban; "Characterization of Industrial Onion Wastes (Allium cepa L.): Dietary Fibre and Bioactive Compounds"; Plant Foods for Human Nutrition 66 (1): 48-57, 2011.

DSM successfully acquires 51% stake in AGI Corporation (Taiwan)

Royal DSM N.V. announced that it has successfully acquired a 51% stake in AGI Corporation of Taiwan (AGI) through a subscription for newly to be issued shares combined with a public tender offer for about € 41 million in total. The acquisition was announced in December 2010 and is consistent with DSM's strategic focus on high growth economies, sustainability, innovation and partnerships.

AGI offers a broad range of environmentally friendly UV (ultraviolet) curable resins and other products. These products are used in coatings and inks for wood, flooring, plastic and graphic arts applications. AGI reported net sales in 2010 of NTD 4,050 million (approximately € 97 million). AGI continues to be listed on the emerging companies board of the GreTai Securities Market in Taipei. DSM will consolidate AGI in its financial statements.

Dimitri de Vreeze, President of DSM Resins & Functional Materials, commented: "The acquisition of 51% of AGI allows DSM to strengthen its UV resins technology platform. UV curing is environmentally friendly and the winning technology for the future. UV coatings and ink systems have a low eco-footprint in combination with high-performance low total operational costs. This expansion in UV coatings and ink system markets will allow DSM to realize its ambition to become the global leader in sustainable and innovative resins, the key ingredients of paints and inks. We look forward to working with AGI and its shareholders, management and employees."

Bill Chung, Chairman of AGI Corporation said: "We are looking forward to work with DSM to provide better services to the market and grow the UV business together. DSM and AGI share the same dream of being a leading UV player fulfilling the needs of our customers with a winning and innovative technology toolbox. Via this strategic alliance strong momentum will be created to realize this dream. AGI is a strong Asian company and has in depth knowledge about the high growth economies in this part of the world. This combined with DSM's global market know how and asset infrastructure creates a unique combination. Being complementary to each other, we are confident that DSM-AGI is going to generate a compelling, and high-potential future for AGI's customers, shareholders and employees."


Benzene Achieves Record Sales

Benzene, a colorless liquid, is the precursor for numerous chemical compounds. The global benzene market will see dynamic growth: According to the new report from the market research institute Ceresana Research, the global demand for benzene will rise to approximately 6 million tonnes by 2018. In addition, global revenues are anticipated to increase to US$52.6 billion by 2018. “Benzene revenues will substantially exceed the 2007 peak level as soon as in 2011,” expects Oliver Kutsch, CEO of Ceresana.

Production capacities of benzene and its downstream products will be expanded above all in the Middle East. Ceresana Research forecasts that the Middle East will see its share of worldwide production grow to 3.7 percent. Moreover, the demand for benzene is increasing significantly in countries such as Saudi Arabia or Kazakhstan. However, the global market is dominated by the Asia-Pacific region, which already accounts for almost half of the global demand for benzene. China is rising to become the world’s greatest benzene consumer and will most likely displace the U.S. to the second place in 2014. In contrast, benzene is increasingly replaced for environmental and health reasons in established industrial countries.

More than half of the global benzene production is used by ethylbenzene manufacturers. Ethylbenzene is primarily used to produce styrene. In turn, styrene is mainly processed into polystyrene plastics, such as EPS foams for insulating sheets and packaging. The second-largest benzene market is the production of cumene, which accounts for approximately 20 percent of all demand. Cumene is a precursor for bisphenol A, phenolic resins, and methyl methacrylate. Further applications of benzene are in cyclohexane, which is used to produce nylon fibers, and in nitrobenzene, used for producing aniline. In addition, benzene is used as an extracting agent, solvent, laboratory chemical, and additive in gasoline.

The practice-oriented study of Ceresana Research gives a concise overview of the benzene market development – worldwide and in the individual world regions. Demand, production, imports, exports, revenues, and prices are analyzed. 35 countries are studied in detail. Particular emphasis is placed on the main application areas of benzene: ethylbenzene, cumene, cyclohexane, alkylbenzene, and nitrobenzene. The useful list of manufacturers in Vol. II includes 143 profiles of the most important benzene producers. The study, available in English or German, forecasts market opportunities and risks up to 2018.