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.

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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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Abcc10 may be effective in extending the effectiveness of anticancer drugs

ScienceDaily (May 16, 2011) — Today's anticancer drugs often work wonders against malignancies, but sometimes tumors become resistant to the effects of such drugs, and treatment fails. Medical researchers would like to find ways of counteracting such resistance, but first they must understand why and how it happens. New findings by Fox Chase Cancer Center researchers identify one protein, Abcc10 (also known as Mrp7), as being intimately involved in resistance to certain drugs used to treat breast, ovarian, lung, and other cancers. The results suggest that blunting the activity of Abcc10 might help counter resistance and extend the effectiveness of these anticancer drugs.

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The findings appear in the May 16, 2011 issue of the journal Cancer Research.

In earlier work, Elizabeth A. Hopper-Borge, Ph.D., an assistant professor at Fox Chase, showed that Abcc10 confers resistance to a number of anticancer agents, particularly taxanes, which include paclitaxel (Taxol) and docetaxel (Taxotere). These drugs--originally derived from the Pacific yew tree--work by disrupting cell division, thus arresting the growth and spread of tumors. The initial finding that Abcc10, a member of a ubiquitous family of proteins called ATP-binding cassette transporters, thwarts taxanes' anti-tumor activity was something of a surprise, says Hopper-Borge, because none of the other family members seem to have that ability.

In the new research, Hopper-Borge and colleagues wanted to further explore, in both cultured cells and mice, the role of Abcc10. They developed a "knockout" mouse, in which the gene that codes for Abcc10 was missing, or knocked out. These mice appeared normal and healthy in every other respect, suggesting that Abcc10 is not essential for overall health and survival.

The researchers isolated cells from the knockout mice and tested the cells' reactions to taxanes and two other anticancer drugs, vincristine and Ara-C. Compared to cells from normal mice that still possessed the gene for Abcc10, the knockout mouse cells were much more sensitive to the drugs.

Abcc10 and its ilk work by pumping drugs out of cells, so one might expect to see the drugs accumulating in cells that lack Abcc10, and that's exactly what Hopper-Borge's group saw. It had been suggested that other proteins might take over for Abcc10 if that protein were knocked out, but the researchers found no evidence suggesting that had happened.

Next, the research team studied the effects of one particular taxane, paclitaxel, on mice and found that the knockout mice were more sensitive to the drug, as reflected in body weight, white blood cell count, and ability to survive escalating doses of the drug.

"After seeing the effects on white blood cells, we decided to look at the tissue types that produce white blood cells to see if we could actually see differences there," says Hopper-Borge. As expected, knockout mice treated with paclitaxel had smaller spleens and thymus glands and underdeveloped bone marrow, compared to normal mice treated with the same drug.

The results provide the first evidence from living organisms that Abcc10 is a cell's built-in protection against the effects of powerful drugs, and raises the possibility of using Abcc10 inhibitors to break down that resistance and sensitize tumor cells to anticancer agents. The fact that mice lacking the protein have no obvious health problems is encouraging, suggesting that Abcc10 inhibitors could be used in human patients without causing side effects that might be expected to result from interfering with the pump's normal functions.

Several Abcc10 inhibitors already have been identified, but they also inhibit other cellular transporters, which could have deleterious effects. For that reason, Hopper-Borge thinks the best approach may be developing inhibitors that work only in tumor cells or coming up with compounds that modulate, rather than completely inhibit the protein's activity.

But using such treatments in patients is still far in the future, she emphasizes.

"I'd like to stress that we did this work in a mouse model," Hopper-Borge says. "Our results so far suggest that this protein may be a clinically relevant target, but we need to do more studies to find out for sure."

Co-authors on the study include Timothy Churchill, Chelsy Paulose, Emmanuelle Nicolas, Joely D. Jacobs, Olivia Ngo, Andres J. Klein-Szanto and Martin G. Belinsky of Fox Chase; Yehong Kuang of Central South University, Changsha, China; Alex Grinberg and Heiner Westphal of the National Institute of Child Health and Human Development; and Gary D. Kruh of the University of Illinois at Chicago.

The research was supported by the National Institutes of Health.

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