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Ho Ho the Mistletoe, Decreasing HSP


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December 21, 2012

The semiparasitic, poisonous plant Viscum album—also known as mistletoe—has been used in small doses for centuries to treat ailments from epilepsy to infertility. Now it’s one of the most prescribed complementary cancer therapies in Germany and Switzerland. But the mechanisms of its therapeutic effect, if any, are unclear.

In a paper published last August in Genetics and Molecular Research, researchers have sussed out one way the plant might conquer cancer: it targets heat shock proteins that protect cancer cells from early death. “Our results showed that mistletoe extract reduced expression of these stress proteins,” said study author Evren Önay Uçar from Istanbul University.

Stressful conditions in normal cells trigger the expression of heat shock proteins (HSP), which encourage cell recovery by helping to repair or remove damaged proteins, among other functions. For example, HSP27 is a molecular chaperone that assists in cellular responses against stressors such as heat shock and oxidative stress and 14-3-3 proteins are a type of heat-shock protein that takes part in many cellular processes.

But these proteins’ altruism turns dark when they are expressed in cancer cells, protecting them from apoptosis. “Expression of Hsp27 and 14-3-3 proteins is clearly up-regulated in some cancer types,” says Önay Uçar. “They may play an important role in these cancer cells’ response to drugs and other therapeutic treatments.”

Previous work has shown that refined extracts from various parts of the mistletoe plant have shown antiviral, anticancer, and apoptosis-inducing effects. Önay Uçar’s research has found that mistletoe is also an antioxidant; other studies have shown that some antioxidants reduce expression of stress proteins like heat shock proteins.

So Önay Uçar harvested mistletoe plants that were growing on lime trees in northern Istanbul, and prepared an extract of the leaves in methanol. Using a C6 glioma cell line, she heat-shocked the cells to overexpress their HSPs, and assessed HSP expression levels by Western blot. She also tested for apoptosis by examining caspase-3 activation.

As a result, she found that cancer cells that had been pretreated with a nontoxic dose of mistletoe extract before heat shock expressed significantly lower levels of HSP27, 14-3-3 beta, 14-3-3 gamma, and 14-3-3 zeta, while apoptosis via caspase-3 activation increased.

“This paper suggested for the first time that mistletoe extract is able to downregulate expression of HSP27 and 14-3-3 chaperone proteins, and induce apoptosis in a glioma cell line,” said Önay Uçar.

While the U.S. Food and Drug Administration has not approved mistletoe as a treatment for any disease, and clinical trials showing benefit are not robust, trials testing the plant’s effect on patients with cancer are in the works.

Meanwhile, Önay Uçar plans to repeat the study on other types of cancer cells, as well as with anticancer drugs. “Elevated HSP levels in tumor cells are suggested to be responsible for increased chemotherapy resistance and poor prognosis for cancer patients,” she said. “The inhibition of stress proteins like HSP27 or 14-3-3 proteins might be new targets for cancer therapy.”


1. Uçar, E. Ã., N. Arda, and A. Aitken. 2012. Extract from mistletoe, viscum album l., reduces hsp27 and 14-3-3 protein expression and induces apoptosis in c6 rat glioma cells. Genetics and molecular research : GMR 11(3):2801-2813.

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