Cancer Cells Could Be Turned Against Themselves Using Their Own Carbon Monoxide

At the RIKEN Pioneering Research Institute in Japan, a team led by Katsunori Tanaka has shown in cultured cells that a tumor's own waste gas can be turned into the weapon that kills it. The proof-of-concept study, published in Nature Communications, describes a synthetic compound that uses excess carbon monoxide inside cancer cells to build an anti-cancer drug on the spot.

The idea answers a familiar problem. Traditional chemotherapy has to kill cancer without causing harmful side effects, and its side effects can end up being just as damaging as the disease. Tanaka and other researchers are working on technologies that target tumors selectively. His goal at RIKEN is to eventually inject patients with harmless compounds, which cancer cells would take up and then use to make drugs on the fly, rather than injecting the drugs themselves.

Carbon monoxide is the hook. Best known as a poisonous gas from burning gasoline in car engines, it has recently been found to be produced by many types of cancer cells as well. That makes it a kind of cancer biomarker, though only if it can be detected. Healthy cells do not carry the same excess, so a reaction that depends on the gas would, in principle, run only in tumor cells.

The team, from the Biofunctional Synthetic Chemistry Laboratory, built the reaction around organometallic complexes called palladacycles. With carbon monoxide, palladacycles can make an organic compound called phenanthridinone. Several phenanthridinone derivatives are cytotoxic and have already been used in anti-cancer drugs. The obstacle was that a palladacycle placed inside a tumor cell does nothing, because the metal catalyst at its center is quickly destroyed by molecules such as glutathione.

Tanaka's lab specializes in metal-catalyzed reactions in living systems, and it drew on its earlier work to solve the problem. The researchers placed a palladacycle inside albumin, a common blood protein. The resulting albumin–palladacycle complex can travel safely through the blood, and when it enters cells the palladium catalyst stays protected.

The testing went in stages. The team first screened a collection of palladacycles to find the one that yielded the most phenanthridinone. They then incubated the albumin–palladacycle complex for 48 hours with human liver, cervical, breast and lung cancer cell lines, and with one non-cancerous cell line. The product appeared in the cancer lines but not in the normal cells. That indicated the complex shielded the catalyst from glutathione and that the targeting worked. A few adjustments made sure the product detached from the complex and moved freely within the cell.

Next, the researchers modified the complex so it would generate a particular phenanthridinone that is highly toxic and used in anti-cancer drugs. In the liver cancer cell line, they saw the drug form inside the cells, and the cells then suffered its toxic effects.

One concern was blood itself, which carries carbon monoxide. If the reaction fired in transit, the toxic compound could kill blood cells before the complex reached a tumor. In testing, blood stayed free of the drug, presumably because carbon monoxide in blood is bound to hemoglobin and unavailable for the reaction.

"This work represents an important advance in therapeutic in vivo synthetic chemistry," Tanaka said, describing a strategy in which molecules present in or generated by the body, including disease-associated metabolites, serve as chemical feedstocks to make therapeutic molecules directly at the site of disease. So far the evidence comes only from cultured cell lines. The next step is animal models, which will show whether the approach holds up in a living body.