Anticancer drug strategy: making cells choke on copper

What do cancer cells have in common with horseshoe crabs and Mr. Spock from Star Trek?

They all depend upon copper. Horseshoe crabs have blue blood because they use copper to transport oxygen in their blood instead of iron (hemocyanin vs hemoglobin). Vulcans’ blood was supposed to be green, for the same reason.

Horseshoe Crab (Limulus polyphemus)

Horseshoe crabs and Vulcans use copper to transport oxygen in their blood. Cancer cells seem to need the metal more than other cells.

To be sure, all our cells need copper. Many human enzymes use the metal to catalyze important reactions, but cancer cells seem to need it more than healthy cells. Manipulating the body’s flow of copper is emerging as an anticancer drug strategy.

A team of scientists from University of Chicago, Emory and Shanghai have developed compounds that interfere with copper transport inside cells. These compounds inhibit the growth of several types of cancer cells, with minimal effects on the growth of non-cancerous cells, the researchers report in Nature Chemistry.

“We’re taking a tactic that’s different from other approaches. These compounds actually cause copper to accumulate inside cells,” says co-senior author Jing Chen, PhD, professor of hematology and medical oncology at Emory University School of Medicine and Winship Cancer Institute.

Other compounds that soak up copper instead have already been in clinical trials, with mixed results. The drug tetrathiomolybdate has shown potential for preventing breast cancer recurrence in one study, but other studies have been disappointing.

Even though copper plays an essential role in several enzymes, having too much free-floating copper inside the cell is toxic. Cells carefully shepherd copper with proteins called chaperones, which were targets for the chemicals described in the Nature Chemistry paper.

Scientists led by Chuan He, PhD at University of Chicago and Hualiang Jiang, PhD, director of Shanghai Institute of Materia Medica, designed compounds that could interfere with two copper chaperones, Atox1 and CCS. They teamed up with Chen and his colleagues to test their anticancer effects.

These compounds inhibited the growth of leukemia cells, and lung, breast and head and neck cancer cell lines, but did not interfere with non-cancerous skin, lung or breast cells. They also slowed the growth of tumors created when human lung cancer cells were grafted into mice. Additional toxicology studies will be needed before clinical trials.

The chaperone inhibitors caused an increase in the levels of copper inside cells, in contrast with the decrease in copper levels seen with tetrathiomolybdate. As a result, chaperone inhibitor-treated cells also displayed an increase in reactive oxygen species and oxidative stress, and a decrease in production of ATP, the cell’s energy currency.

Previous studies have suggested that restricting access to copper may interfere with angiogenesis, or cancer cells’ ability to attract new blood vessels. However, the effects coming from the copper chaperone inhibitors were intrinsic to cancer cells themselves.

“Cancer cells both produce more reactive oxygen species and are more sensitive to them,” Chen says. “This may account for the preferential anticancer effect of our compounds. In addition, we see interference with synthesis of lipids, which cancer cells need for rapid growth.”

Stu Borman from Chemical & Engineering News reports that the team has licensed one compound they found, called DC_AC50, to Suring Therapeutics in China and also plans to tweak it to develop more-potent versions.

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Posted on by Quinn Eastman in Cancer Leave a comment

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Quinn Eastman

Science Writer, Research Communications qeastma@emory.edu 404-727-7829 Office

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