Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Research sheds light on workings of anti-cancer drug

27.11.2009
Crystal structure shows how drug disables harmful copper in cells

The copper sequestering drug tetrathiomolybdate (TM) has been shown in studies to be effective in the treatment of Wilson disease, a disease caused by an overload of copper, and certain metastatic cancers. That much is known. Very little, however, is known about how the drug works at the molecular level.

A new study led by Northwestern University researchers now has provided an invaluable clue: the three-dimensional structure of TM bound to copper-loaded metallochaperones. The drug sequesters the chaperone and its bound copper, preventing both from carrying out their normal functions in the cell. For patients with Wilson disease and certain cancers whose initial growth is helped by copper-dependent angiogenesis, this is very promising.

This knowledge opens the door to the development of new classes of pharmaceutical agents based on metal trafficking pathways, as well as the further development of more efficient TM-based drugs. The study will be published in Science Express Nov. 26.

"Essential metals are at the center of many emerging problems in health, medicine and the environment, and this work opens the door to new biological experiments," said Thomas V. O'Halloran, the study's senior author and the Charles E. and Emma H. Morrison Professor of Chemistry in the Weinberg College of Arts and Sciences at Northwestern. He and geneticist Valeria Culotta of Johns Hopkins University discovered the first copper chaperone function in 1997.

O'Halloran and his research team studied the copper chaperone protein Atx1, which provides a good model of copper metabolism in animal cells. "We wondered what the drug tetrathiomolybdate did to copper chaperones -- proteins charged with safely ferrying copper within the cell -- and what we found was most amazing," O'Halloran said. "The drug brings three copper chaperones into close quarters, weaving them together through an intricate metal-sulfur cluster in a manner that essentially shuts down the copper ferrying system."

The nest-shaped structure of the metal-sulfur cluster discovered by the researchers was completely unanticipated.

"When we mixed TM together with copper chaperone proteins in a test tube, the color of the solution changed from light orange to deep purple," said Hamsell M. Alvarez, the paper's first author and a former doctoral student in O'Halloran's lab, now with Merck & Co., Inc. "The sulfur atoms in the tetrathiomolybdate bound to the copper atoms to form an open cluster that bridged the chaperone proteins. In this manner, three copper proteins were jammed onto one thiomolybdate."

Alfonso Mondragón, professor of biochemistry, molecular biology and cell biology in the Weinberg College of Arts and Sciences, and graduate student Yi Xue, both co-authors of the paper, solved the three-dimensional crystal structure using protein X-ray crystallography. This is the first example of a copper-sulfide-molybdenum metal cluster protein.

Based on the structure and additional experiments, the scientists propose that the drug inhibits the traffic of copper within the cell because of its ability to sequester copper chaperones and their cargo in clusters, rendering the copper inactive.

"We conclude that the biological activity of tetrathiomolybdate does not arise from a simple copper sequestering action but through a disruption of key protein-protein interactions important in human copper metabolism," Alvarez said.

Inorganic elements, such as copper, zinc and iron, are vital to the healthy functioning of all cells in living organisms. But they are high-maintenance nutrients, and too much can be toxic, as is the case in Wilson disease, a genetic disorder that prevents the body from getting rid of extra copper and leads to liver and neurological problems.

Copper also is an important cofactor for tumor angiogenesis, the process of growing new blood vessels to feed the tumor. Researchers believe this is why tetrathiomolybdate has shown promise as an anti-cancer drug.

The chain of discovery that led to the use of tetrathiomolybdate as a therapeutic agent began in the 1930s when cows grazing in certain types of pastures in England developed neurological problems. This trouble was then linked to other neurological problems with sheep grazing on certain soils in Australia. It was found that molybdate, a non-toxic compound present in the grass of these pastures, when consumed in excessive amounts by the ruminants, led to copper deficiencies and neurological problems in the animals.

As copper overload disorders such as Wilson disease were discovered in humans, physicians used molybdenum chemistry focusing on tetrathiomolybdate to lower copper levels in the body. (Tetrathiomolybdate is an inorganic small molecule first synthesized by J. J. Berzelius in 1826.)

Tetrathiomolybdate is the active pharmaceutical agent in a well-tolerated drug that has shown activity for the treatment of Wilson disease and now is in phase II clinical trials as an anti-cancer drug.

TM also has been examined in recent studies where copper dysregulation is implicated in the pathogenesis of neurodegenerative diseases such as familial amyotrophic lateral sclerosis (ALS), Parkinson's disease, multiple sclerosis and Alzheimer's disease as well as primary pulmonary hypertension and left ventricular hypertrophy associated with type II diabetes. Copper modulating agents including TM have been shown to be active in animal models of these diseases providing a rationale for advancing tetrathiomolybdates into clinical evaluation in these areas.

O'Halloran also is director of Northwestern's Chemistry of Life Processes Institute and serves as associate director for basic science research at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Mondragón is a member and Alvarez was a Malkin Fellow of the Lurie Cancer Center.

The Science paper is titled "Tetrathiomolybdate Inhibits Copper Trafficking Proteins Through Metal Cluster Formation." In addition to O'Halloran, Alvarez, Mondragón and Xue, other authors of the paper are Chandler D. Robinson, Mónica A. Canalizo-Hernández and Rebecca G. Marvin from Northwestern, and Rebekah A. Kelly and James E. Penner-Hahn from the University of Michigan.

Megan Fellman | EurekAlert!
Further information:
http://www.northwestern.edu

More articles from Life Sciences:

nachricht Multi-institutional collaboration uncovers how molecular machines assemble
02.12.2016 | Salk Institute

nachricht Fertilized egg cells trigger and monitor loss of sperm’s epigenetic memory
02.12.2016 | IMBA - Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

Im Focus: Molecules change shape when wet

Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water

In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...

Im Focus: Fraunhofer ISE Develops Highly Compact, High Frequency DC/DC Converter for Aviation

The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.

Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

UTSA study describes new minimally invasive device to treat cancer and other illnesses

02.12.2016 | Medical Engineering

Plasma-zapping process could yield trans fat-free soybean oil product

02.12.2016 | Agricultural and Forestry Science

What do Netflix, Google and planetary systems have in common?

02.12.2016 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>