Researchers harness cancer cells' carbon monoxide to produce anticancer drug

What if we could use a cancer's own byproduct to make drugs that destroy tumor cells from the inside? That is exactly what Katsunori Tanaka and his team have done at the RIKEN Pioneering Research Institute (PRI) in Japan. Published in Nature Communications, the proof-of-concept study describes how a synthetically designed compound uses the excess carbon monoxide produced in tumor cells to trigger the production of anti-cancer drugs within the cells themselves. Treatment methods based on this technique would be ideal as it selectively targets tumors and avoids harming healthy cells.

The concept

For cancer treatment to be the most effective, it must kill the cancer without producing harmful side effects. For traditional chemotherapies, the side effects may end up being just as harmful as the cancer. Tanaka and like-minded researchers are trying to improve treatments by devising new technologies that selectively target tumors. At RIKEN, rather than injecting the body with cancer-killing drugs, Tanaka's goal is to eventually inject patients with harmless compounds that can be used to make drugs on the fly after they are picked up by cancer cells.

Most of us know about carbon monoxide, a poisonous gas commonly produced by the burning of gasoline in car engines. Recently, research has shown that many types of cancer cells also produce this gas. This makes carbon monoxide a kind of cancer biomarker, but only if it can be detected. In the newly published experiments, scientists in the Biofunctional Synthetic Chemistry Laboratory at RIKEN PRI tested a system for bringing a metal catalyst into cells and then using it and excess carbon monoxide to make a toxic bioactive compound. Because cancer cells have excess carbon monoxide and healthy cells do not, only the cancer cells are exposed to the cytotoxic drug.

Designing the drug delivery system

The team focused on carbon monoxide because it can be used by organometallic complexes called palladacycles to make the organic compound phenanthridinone. Several phenanthridinone derivatives are cytotoxic, meaning they kills cells, and have already been used in anti-cancer drugs. But simply putting palladacycles inside a tumor cell does nothing because the metal catalyst in the center is quickly destroyed by special molecules inside cells, such as glutathione.

To overcome this problem, Tanaka turned to his lab's unique specialty: in vivo metal-catalyzed reactions. Building off their previous studies, they placed a palladacycle inside albumin, a common protein found in the blood. The albumin–palladacycle complex can thus safely travel in the blood, and when it enters cells, the metal palladium catalyst is protected.

The proof of concept

The researchers tested this system at many stages. First, they screened a collection of palladacycles to find the one that yielded the most phenanthridinone. Next, they incubated the albumin–palladacycle complex for 48 hours with human liver, cervix, breast, or lung cancer cell lines, as well as with a non-cancerous cell line. After the 48 hours, they detected the desired product in the cancer lines, but not in the normal cells. This showed both that the complex protected the catalyst from glutathione and that targeting was successful – the reaction only occurred in the cancer cells. A few adjustments ensured that the product would detach from the complex and freely move about the cell.

Once this was confirmed, they tweaked the albumin–palladacycle complex so that the reaction produced a specific kind of phenanthridinone that is highly toxic and used in anti-cancer drugs. When tested in the liver cancer cell line, they observed the drug being produced inside the cells, which subsequently suffered from the toxic drug's effects.

Carbon monoxide in blood was a potential concern as accidentally triggering production of the toxic in blood during transport would kill the blood cells before it arrived at the target location. However, when tested, blood remained free of the drug, presumably because carbon monoxide in blood is bound to hemoglobin, making it unavailable for the reaction.

This work represents an important advance in therapeutic in vivo synthetic chemistry. In our therapeutic strategy, molecules naturally present or generated within the body-including disease-associated metabolites-are used as endogenous chemical feedstocks to synthesize therapeutic molecules directly at the site of disease."

Katsunori Tanaka, RIKEN Pioneering Research Institute (PRI) 

The next step is to move from cultured cell lines to animal models.