Withaferin A’s anti-metastatic properties could form the basis of drug regimens aimed at preventing cancer recurrence, and researchers are planning further tests with breast cancer and other cancer types. The results are published online ahead of print in the International Journal of Cancer.
“Most patients who die from cancer die because of metastases, not from the primary tumor,” says senior author Adam Marcus, PhD, assistant professor of hematology and medical oncology at the Winship Cancer Institute of Emory University and a Georgia Cancer Coalition Scholar. “Our objective was not to find a way to kill cells, but instead, prevent them from migrating and invading other tissues.”
The first author of the paper is postdoctoral fellow Jose Thaiparambil. Other contributors included Paula Vertino, Donald Harvey, biostatistician Mourad Tighiouart, and veterinary pathologist Anapatricia Garcia.
Withaferin A comes from Withania somnifera, also known as Ashwagandha, whose roots are used in Ayurvedic medicine, which is one of the world’s oldest medical systems. It originated in India and has evolved there over thousands of years.
Marcus says his team focused on withaferin A because it was known to bind the protein vimentin, a protein that is overproduced in cancer cells, especially those from invasive tumors. Tumors that overproduce vimentin are more likely to metastasize.
Marcus says his team looked for a concentration of withaferin A that does not kill cells, but does prevent migration and invasion in laboratory tests. Withaferin A appears to prevent vimentin from forming a network within the cell. In mice, withaferin A prevents breast cancer cells from spreading to the lung. Testing a set of chemically modified versions of withaferin A revealed that a particular region of the molecule is important for its anti-invasive activity and ability to disrupt vimentin.
In the 1990s, scientists found that mice lacking vimentin develop normally – a surprising result for a protein that looks like a basic building block of the cell. This suggests that clinical use of withaferin A could have minimal toxic side effects. It may be possible for withaferin A to be taken in low doses over long periods of time to prevent cancer metastasis, either in combination with chemotherapy or after these treatments are over.
Marcus says his laboratory is now investigating whether Withania somnifera contains other compounds that work together with withaferin A, comparing the root extract against purified withaferin A. In addition, other compounds identified independently that bind vimentin might have even more favorable properties, he says.
This work was supported by the Godfrey Charitable Trust, the American Cancer Society, the National Center for Complementary and Alternative Medicine and Golfers against Cancer.
J.T. Thaiparambil et al. Withaferin A inhibits breast cancer invasion and metastasis at sub-cytotoxic doses by inducing vimentin disassembly and serine 56 phosphorylation. Intl. J. Cancer. (2011). DOI: 10.1002/ijc.25938
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Writer: Quinn Eastman
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