Heavy Metal

A chemotherapy drug sets in motion a series of disruptions that lead to cancer cell death.

By Lori Oliwenstein

It is one thing to have a good, effective treatment for a specific cancer. It is another thing altogether to know how and why that drug works. When researchers have the latter, they have not just a single drug, but also the potential to create many drugs and to treat a much broader group of cancers than most individual drugs can manage.

That is precisely what Joseph Hacia, Ph.D., assistant professor of biochemistry and molecular biology at the Keck School of Medicine of USC, and his colleagues accomplished with the chemotherapy drug motexafin gadolinium.

According to the research done by Hacia’s team, motexafin gadolinium, or MGd—currently used primarily as a treatment for cancer that has spread, or metastasized, to the brain in cases of non-small cell lung cancer—works to thwart cancer cells by disrupting key enzymes involved in cellular metabolism.

The cellular disruption results in increases in the amount of zinc available inside the cancer cells, and because zinc is involved in protein structure and function, leads to inhibition of enzyme activity and to the death of the cells.

To gain a better understanding of the mechanism of action of this novel chemotherapeutic agent, the researchers looked at gene expression profiles and other biochemical properties of cells from human lung, prostate and lymphoma cancer cell cultures that had been treated with MGd. They found that the drug created oxidative stress in the tumor cells, and that one of the results of that oxidative stress was an increase in the levels of expression of the genes that produce metallothioneins, which are proteins that can bind to and transport heavy metals such as zinc.

This led the researchers to try to find the reason for the increase in metallothioneins—and they found it in a significantly increased level of free (not protein-bound) zinc in the cells. That zinc, it turns out, not only prompts metallothionein production, but also acts to inhibit an enzyme called thioredoxin reductase. And thioredoxin reductase is an important component in the cell’s antioxidant system, as well as in DNA synthesis.

In other words, introduction of the drug MGd into tumor cells results in the inhibition in those cells of thioredoxin reductase, an enzyme that is key to the replication and survival of cells. And that ultimately leads to cell death, otherwise known as apoptosis.

Thus, the researchers noted, the use of MGd leads to the death of cancer cells via disruption of critical enzymes needed for cell survival and replication.

“We have increased the understanding of this drug’s mechanism of action,” Hacia says of the study, adding that this enhanced comprehension also may “provide support for the hypothesis that agents that disrupt metabolism and increase intracellular zinc levels have potential applications as anticancer therapeutics.”

And that, Hacia notes, may one day lead to an entire class of drugs that work much as MGd does, or to the application of MGd itself to a much wider range of cancers whose cells are vulnerable to this specific type of metabolic mayhem. ?

The Donald E. and Delia B. Baxter Foundation and the V Foundation for Cancer Research support Hacia’s research. Pharmacyclics Inc. manufactures motexafin gadolinium under the brand name Xcytrin. A paper describing these findings was published in the May 1 issue of the journal Cancer Research.