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 Not of Divided Mind
19.01.2017 | Hertie-Institut für klinische Hirnforschung (HIH)

nachricht CRISPR meets single-cell sequencing in new screening method
19.01.2017 | CeMM Forschungszentrum für Molekulare Medizin der Österreichischen Akademie der Wissenschaften

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Traffic jam in empty space

New success for Konstanz physicists in studying the quantum vacuum

An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...

Im Focus: How gut bacteria can make us ill

HZI researchers decipher infection mechanisms of Yersinia and immune responses of the host

Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Sustainable Water use in Agriculture in Eastern Europe and Central Asia

19.01.2017 | Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

 
Latest News

New Study Will Help Find the Best Locations for Thermal Power Stations in Iceland

19.01.2017 | Earth Sciences

Not of Divided Mind

19.01.2017 | Life Sciences

Molecule flash mob

19.01.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>