Many drugs used to fight cancer are based on metals. But such organometallic agents are generally thought to have low specificity for potential targets in cells, raising concerns that they may inflict collateral damage on healthy cells. Now scientists have identified an organometallic compound based on ruthenium that has a specific anticancer effect, which suggests that such organometallic agents can be more specific than previously thought. The scientists recently detailed their findings online in the journal Angewandte Chemie International Edition.
The number of platinum-based drugs far outnumbers the use of any other organometallic cancer drug, according to study senior author Christopher Gerner, a bioanalytical chemist at the University of Vienna. Platinum-based drugs alone treat roughly 50 percent of cancer chemotherapy patients.
Gerner and his colleagues wanted to investigate the largely unexplored class of potential organometallic anticancer compounds based on metals other than platinum. They focused on a ruthenium-based agent, named plecstatin, that they had recently discovered.
The scientists immobilized plecstatin on beads and exposed it to the inner contents of human colon cancer carcinoma cells to uncover which molecules might bind to it. Some cells were given high, sub-toxic doses of plecstatin beforehand, while others were not. Comparing the response of the contents from these pre-treated cells with that from the untreated cells helped Gerner and his colleagues narrow down what plecstatin might react with.
Unexpectedly, the scientists discovered that plecstatin specifically targeted a protein labeled plectin, that helps make up the scaffolding within cells. “We narrowed it down to plectin from 2,000 or 3,000 candidates,” Gerner says.
The researchers found that plecstatin’s interactions with plectin could affect the architecture of cells. For instance, mouse skin cells known as keratinocytes became smaller and rounder in shape. In cells that were genetically modified to no longer make plectin, plecstatin no longer had these effects, confirming that plecstatin specifically targeted plectin.
Further work revealed that plecstatin disrupted the organization of structures known as non-mitotic microtubules. In cells given plecstatin, these structures no longer arranged themselves in parallel rows, but in dense, curved networks encircling the cell nucleus. Cancers are often characterized by uncontrolled cell migration. So, by targeting part of the mechanisms of cell migration, the scientists reasoned that plecstatin would interfere with malignant cells but spare normal cell function, Gerner says.
Previous research found that plectin deficiencies reduced the mobility and invasiveness of pancreatic, urinary bladder and colon cancer cells. In experiments, Gerner and his colleagues found that tumor cells spread 46 to 62 percent less in a gel matrix over 96 hours when given plecstatin while leaving normal cell function alone, Gerner says.
In mice injected with tumor cells, orally administered plecstatin could significantly reduce the size and weight of colon and melanoma tumors, the researchers found. “To the first of our knowledge, we’ve identified the molecular interaction partner of such an agent, completely understood the mode of its interactions, and the logical consequences of these interactions,” Gerner says.
He suggests the main reason that scientists previously thought metal-based anticancer drugs had overly broad effects was because they failed to find what these drugs specifically targeted. “Maybe it’s not that these drugs are unspecific—maybe it’s that we are using them in an unspecific fashion,” Gerner says.
Even so, future plecstatin work should take note of the fact that plectin is found in many normal cells, says Michelle Hill, head of the cancer proteomics group at the University of Queensland Diamantina Institute in Brisbane, Australia, who did not take part in this research. “Does the drug affect non-malignant cells?” she asks.
Gerner now plans to analyze metal-based drugs in greater detail to see if they actually have specific targets within cells. “If we can know the mode of action of these powerful drugs,” he says, “we can use them in a wiser, targeted way to dramatically increased the chance of having desired, long-lasting effects.”