Anticancer effect of mushrooms demonstrated

ScienceDaily (June 4, 2011) — City of Hope researchers have investigated compounds in natural foods for their potential anticancer benefits, with a focus on food items that are easily found in grocery stores to ensure greater access and availability. Shiuan Chen, Ph.D., associate chair and professor of City of Hope's Department of Cancer Biology, identified phytochemicals in mushrooms that block the ezyme aromatase from producing estrogen. Controlling aromatase activity can help decrease estrogen levels, which controls and kills hormone-dependent breast cancers. In addition, mushrooms also demonstrate the ability to inhibit cancer call activity and slow tumor growth.

See Also:Health & MedicineBreast CancerCancerLung CancerPlants & AnimalsMiceVeterinary MedicineFungusReferenceHormone replacement therapyMenopauseBreast cancerMetastasis

Promising data from two early stage studies using mushrooms in preventing breast cancer recurrence and treatment of lung cancer are being presented at the 2011 Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago, running from June 3 through 7.

Research highlights include:

"A dose-finding clinical trial of mushroom powder in postmenopausal breast cancer survivors for secondary breast cancer prevention."

An estimated one in five breast cancer survivors will experience a recurrence of his or her cancer within 10 years of treatment of the initial cancer diagnosis. With more than 80 percent of cancers diagnosed in women after menopause being hormone-dependent, there is a need for preventive treatments to lower that risk. The natural aromatase-inhibiting qualities of mushrooms noted in preclinical studies has the potential to offer a dietary intervention that may help prevent recurrence of hormone-dependent breast cancers.

Postmenopausal breast cancer survivors who were cancer free after completion of cancer therapy were enrolled in the trial. Groups received a 12-week course of white button mushroom extract at 5, 8, 10 or 13 gram doses. Because aromatase inhibition leads to a decrease in estrogen levels, a specific estrogen called estradiol was monitored and response was defined as a greater than 50 percent decrease in free estradiol levels in the blood circulation. Mushroom extract was well tolerated at all doses. However, no dose could be identified that met response criteria. In spite of this, a measurement of aromatase activity developed by Dr. Chen suggested some modest transient aromatase inhibition that lasted longest at the highest dose level (6 hours), suggesting that weak aromatase inhibition by mushrooms is achievable in patients, but that likely much higher amounts would be needed to achieve a clinically significant result.

"City of Hope developed a test sensitive enough to track aromatase activity that is sensitive to short-term changes, and we were able to successfully utilize that in the trial," said Melanie Palomares, M.D., M.S., assistant professor of the High Risk Breast Program at City of Hope, and lead author of the study. "Over the course of 12 weeks, we were able to observe phytochemical activity, but not at high enough concentrations to significantly reduce estrogen levels in our patients. Future studies should focus on more highly concentrated preparations of mushroom extract. Tissue levels of estrogens may also be a better measure than circulating estrogens."

"A phase I study of MM-10-001 in advanced nonsmall cell lung cancer."

Marianna Koczywas, M.D., assistant professor in City of Hope's Department of Medical Oncology & Therapeutics Research, is the principal investigator of a lung cancer study on a novel therapy, MM-10-011, derived from Shiitake Mycelium in mushrooms. The trial is in progress and Koczywas is presenting preliminary data from an interim analysis. MM-10-001 has demonstrated the ability to provoke and immune response specific to tumor cells in laboratory tests. The phase I clinical trial is intended to determine the toxicity of treatment and the highest dose patients can tolerate. This is a first step in three phases of clinical trials in humans to establish the safety, dosing and efficacy of new therapies. To date, 20 patients with advanced nonsmall cell lung cancer have received treatment with escalating doses of MM-10-001, from 5 to 10 to 20 mg, over 28 days.

No severe adverse events were reported. Two patients reported grade 2 fatigue, and one patient each reported loss of appetite, high protein levels in the blood and joint pain. The maximum tolerated dose of MM-10-001 had not been reached at the time of interim analysis.

"The clinical trial is ongoing, but the interim data are promising, with indications that MM-10-001 may be stimulating an immune response against the tumor," said Koczywas. "In a majority of the patients, we observed a possible decrease in interleukin-12 levels corresponding to treatment cycles, suggesting that lower interleukin levels are associated with improved survival."

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Understanding cancer energetics: Researchers solve mystery of Warburg effect

ScienceDaily (June 3, 2011) — It's long been known that cancer cells eat a lot of sugar to stay alive. In fact, where normal, noncancerous cells generate energy from using some sugar and a lot of oxygen, cancerous cells use virtually no oxygen and a lot of sugar. Many genes have been implicated in this process, and now, reporting in the May 27 issue of Cell, researchers at the Johns Hopkins University School of Medicine have discovered that this so-called Warburg effect is controlled.

See Also:Health & MedicineBrain TumorGenesLung CancerLymphomaBreast CancerCancerReferenceSkeletal muscleBlood sugarHeat shock proteinTumor suppressor gene

"It turns out to be a feed-forward mechanism, where protein A turns on B, which in turn goes back and helps A do more," says Gregg Semenza, M.D., Ph.D., the C. Michael Armstrong Professor of Medicine, director of the vascular program at Johns Hopkins' Institute for Cell Engineering and a member of the McKusick-Nathans Institute of Genetic Medicine. "PKM2 normally functions as an enzyme involved in the metabolism of glucose, but in this case we have demonstrated a novel role in the control of gene expression in cancer cells."

Nearly 20 years ago, Semenza's research team discovered that HIF-1 can turn on a number of genes that that help cells survive when oxygen levels fall too low. In addition to genes that contribute to building new blood vessels, HIF-1 also turns on genes involved in the metabolic process that turns glucose into energy. One of those genes, pyruvate kinase M2 or PKM2, catalyzes the first step of this metabolic process and is present only in cancer cells.

To figure out whether and if HIF-1 and PKM2 interact, the team first engineered cells to have or lack HIF-1. They kept them in high or low oxygen for 24 hours and found that cells starved of oxygen, but containing HIF-1, had more PKM2 than cells without HIF-1, suggesting that HIF-1 controls the production of PKM2.

The team then asked if HIF-1 and PKM2 physically interact with each other by isolating one of the two proteins from cells; they found that pulling one out also resulted in the other coming along for the ride, showing that the two proteins do in fact bind to each other.

Knowing that the primary function of HIF-1 is to bind DNA and turn on specific genes, Semenza's team next asked whether PKM2 somehow helped HIF-1 do that. They examined genes known to be activated by HIF-1 in low oxygen after the removal of PKM2 and found that without PKM2, less HIF-1 was bound to DNA.

Now armed with evidence that PKM2 helps HIF-1 turn on genes, the team looked at the activity of genes directly involved in the metabolic pathway that burns so much sugar in cancer cells and compared genes known to be activated by HIF-1 with those not affected by HIF-1. Removing PKM2 from cells had no effect on genes not controlled by HIF-1 but reduced the activity of HIF-1-controlled genes.

"These results were really astounding," says Semenza. "In addition to solving the long-standing mystery of the Warburg effect, we also discovered that PKM2 may play a far broader role in promoting cancer progression than has been appreciated before." This study was funded by the National Heart, Lung and Blood Institute.

Authors on the paper are Weibo Luo, Hongxia Hu, Ryan Chang, Jun Zhong, Matthew Knabel, Robert O'Meally, Robert Cole, Akhilesh Pandey and Gregg Semenza, all of Johns Hopkins.

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