Clues about Cancer: Copper and Anti-Cancer Drugs

These new findings about a copper transporting “pump” within cellular membranes might give scientists a new means of understanding cancerous cells.

The team — composed of San Diego Supercomputer Center research scientists Igor Tsigelny, Yuriy Sharikov, Jerry P. Greenberg, Mark A. Miller, Valentina L. Kouzentsova, Christopher A. Larson and Professor Stephen B. Howell of the UCSD School of Medicine — recently published their findings in journal Cell Biochemistry and Biophysics on May 9.

Cancer is the second leading cause of death in the United States behind heart disease, and accounts for almost one of every four deaths in the nation. According to statistics gathered by The American Cancer Society, 1,638,910 new cases are expected for 2012.

Traditionally, one of the greatest challenges of cancer treatment is finding a way to deliver the effective medicines to the cancerous cells in a person’s body. There have been multiple medicines that destroy cancer cells, but over time are found to have less and less of an effect during cancerous relapses.

But what the team of researchers recently discovered is the importance of one element: copper.

The human copper transporter 1 protein (hTCR1) is a critical pump located in the membranes of human cells that allows for copper atoms to pass into the cell cytoplasm. While the body needs only a small amount of copper, it’s a vital component in creating cellular enzymes and used in the performance of other bodily functions.

In addition, the protein is also used to transport cisplatin, one of the most commonly used anti-cancer drugs. Unfortunately, most anti-cancer drugs lose their effectiveness over time. Some researchers have theorized that this diminishment could be caused by the cancerous cells somehow warping the gateway into the cell.

In order to study this elusive phenomenon of diminishment, the research team created a complete 3D model of the transporter protein to find answers and better understand how the pump works. Tsigelny’s team invented a brand new programming tool named METBIND for their experiment. METBIND scoured the transporter protein samples for traces of any atom that could potentially be a copper ion.

According to the 3D model, the copper transport protein forms a trimer — a structure composed of three proteins — within the cell’s membrane, with the top end sticking outside of the cell and the bottom end extending into the cell’s cytoplasm. This structure, including six receptor sites that signal the cell’s interactions, and nine negatively charged amino acids that latch onto copper ions combine to create a pumping system that allows copper to enter and exit the cell.

“This model is instrumental in understanding the structural composition of the protein,” Stephen Howell said. Howell, a professor of medicine at the UCSD School of Medicine and associate director of clinical research at the UC San Diego Moores Cancer Center, specializes in research that focuses heavily on the interactions of cisplatin and the DNA of tumor cells.

“This has helped us to understand how the transporter uses its components to bring different material into the cell,” Howell said.

These findings could allow researchers to begin mapping out potential blue prints for enhanced anti-cancer drugs that use the hTCR1 and can better travel through the transporter without losing any potency. However, there is still much work to be done.

“It is important to note that we have to be careful that it is only a model,” Howell said. “There are still many different tests and experiments that have to be run.”

“The next steps would be additional mutations in the protein, and see if this inhibits or increases the hTCR1’s capacity to transport copper,” Howell said. “For example, we should predict that if X protein or acid is altered, then it will change the ability to transport copper.”

A stronger version of cisplatin or a new drug in the battle against cancer is still a long time away. However, the findings of Tsigelny and his team provide a new platform from which scientists can explore. Thanks to their efforts, cancer patients in the future may have the possibility of a chemotherapy treatment that lasts longer and acts stronger against a disease that has plagued people around the world.

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