Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Plant compound kills brain tumor cells

30.08.2002


A chemical isolated from a weed that grows in mountain meadows in the western United States kills the cells of an aggressive brain cancer that affects some children. The compound, cyclopamine, blocks a signaling pathway that appears to be important for the survival of medulloblastoma, a form of cancer for which there is no effective treatment.

In an article published in the August 30, 2002, issue of the journal Science, a research team led by Howard Hughes Medical Institute investigator Philip A. Beachy reported that cyclopamine effectively killed cultured mouse medulloblastoma cells and tumors implanted in animals, as well as medulloblastoma cells extracted from human tumors.

“It will be difficult to obtain sufficient quantities of cyclopamine, since it must be extracted and purified from the plant source, Veratrum californicum, the corn lily,” said Beachy, who is at The Johns Hopkins University School of Medicine. “However, we believe that with this study, the evidence is in place to justify an effort to develop a supply so that it can be tested in humans.” Beachy and his colleagues at Johns Hopkins collaborated with researchers from the Fred Hutchinson Cancer Research Center and the University of Washington/Children’s Hospital in Seattle.



Beachy said there are some parallels between cyclopamine and taxol, a drug used to treat breast cancer drug that was initially in short supply because it had to be isolated from the bark of the Pacific yew tree. However, as taxol proved clinically effective, researchers developed an alternate method of partial synthesis of the compound from a more plentiful precursor in the needles that made the drug available in sufficient supply.

Beachy and his colleagues began to explore whether cyclopamine would be effective against medulloblastoma after studies by several groups, including HHMI investigator Matthew Scott and his colleagues at Stanford University, showed that both animals and humans developed tumors, including medulloblastomas, when the Hedgehog signaling pathway was activated. The pathway — named for its key regulatory protein Hedgehog — has long been known to be critical for the growth and differentiation of cells during embryonic development. Scott and his colleagues showed that the tumors they studied consisted of cells that had most likely reverted to a highly proliferative embryonic state, due to a mutation that enabled the activation of the Hedgehog pathway.

The earlier studies showed that the Hedgehog pathway was switched on when the function of one of the pathway’s key genes, called Patched, was lost because of mutation. The protein produced by Patched normally represses a downstream member of the Hedgehog pathway — a protein called Smoothened. Loss of Patched activates the Smoothened protein, turning on the Hedgehog pathway and leading to malignancy.

Beachy and his colleagues had shown previously that cyclopamine blocks the Hedgehog pathway in mouse embryos by inhibiting the activity of Smoothened. Reasoning that the drug might also prevent activation of the Hedgehog pathway in tumors, the scientists tested cyclopamine’s effects on a mouse model developed in Scott’s laboratory, in which one copy of the Patched gene had been disrupted. In these mice, Beachy and his colleagues also removed the gene for p53, a protein that normally triggers the death of cells with damaging mutations. The mice developed medulloblastomas at a young age when expression of the second normal Patched gene was inactivated.

The researchers cultured medulloblastoma cells from the mice and introduced those tumor cells into other mice that had compromised immune systems. “We showed that in these tumor cells we could readily suppress the Hedgehog pathway by treating the tumors with cyclopamine,” said Beachy. “We next decided to see whether the drug would affect tumors that had already been established in mice by injecting the tumor cells. We were pleased to see that cyclopamine could not only block the Hedgehog pathway, but could also stop the growth of these tumors and even cause them to regress,” he said.

The next logical step, said Beachy, was to determine whether cyclopamine was effective in human medulloblastomas. For these studies, co-author James Olson and colleagues at the Fred Hutchinson Cancer Research Center supplied medulloblastoma cells from patients who had undergone surgery to remove the tumors.

“When we treated dispersed cells from these tumors with cyclopamine, they died very quickly, and in fact, the drug appeared to be killing the cells faster than any drug Jim Olson and his colleagues had yet tested,” said Beachy. Also promising, said Beachy, was that in the animal studies, the drug produced no discernible side effects. “Of course, we can’t be sure that there are no side effects at this point, since we can’t ask a mouse how it’s feeling,” said Beachy. “But we saw no obvious adverse effects from the treatment.”

One promising result from the studies of human tumor cells, said Beachy, was that all seven of the human medulloblastomas the scientists tested responded dramatically to cyclopamine. “Genetic studies have shown that only perhaps twenty percent of such sporadic tumors can be assigned to mutations that specifically activate the Hedgehog pathway,” he said. “So, this finding suggests that perhaps activation of the Hedgehog pathway is essential to tumorigenesis, even when it is not specifically switched on by mutation.”

Although Beachy advocates immediate pre-clinical and clinical trials of cyclopamine for medulloblastoma, he cautioned that supply is a critical problem. “Right now, cyclopamine must be purified from the corn lily, and it is unclear how much could be harvested or cultivated,” said Beachy. “Synthesizing cyclopamine might be possible, but it would be very difficult.”

Jim Keeley | EurekAlert!

More articles from Health and Medicine:

nachricht Antibiotic effective against drug-resistant bacteria in pediatric skin infections
17.02.2017 | University of California - San Diego

nachricht Tiny magnetic implant offers new drug delivery method
14.02.2017 | University of British Columbia

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Biocompatible 3-D tracking system has potential to improve robot-assisted surgery

17.02.2017 | Medical Engineering

Real-time MRI analysis powered by supercomputers

17.02.2017 | Medical Engineering

Antibiotic effective against drug-resistant bacteria in pediatric skin infections

17.02.2017 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>