Japanese researchers have developed an experimental cancer-treatment strategy that uses carbon monoxide produced by tumor cells to manufacture anti-cancer compounds inside those same cells. Led by Katsunori Tanaka of the RIKEN Pioneering Research Center (PRI), the team showed in laboratory experiments that an albumin-protected palladium catalyst could trigger drug production in several cancer cell lines without producing the same toxic compounds in non-cancerous cells. The approach remains at an early stage, but it could eventually help target tumors while reducing the side effects associated with conventional chemotherapy.
Using a tumor’s own chemistry against it
One of the central challenges in cancer treatment is destroying malignant cells without harming healthy tissue. Conventional chemotherapy can cause severe side effects because its toxic activity is not always confined to tumors. Tanaka and his colleagues are investigating more selective approaches that could make cancer treatment safer.
The team’s long-term goal is to replace the direct delivery of toxic drugs with relatively harmless compounds that become active only after entering cancer cells. These compounds would use substances already present in a tumor to produce therapeutic agents precisely where they are needed.
Carbon monoxide offers a potential way to achieve this selectivity. The gas is widely known as a toxin produced by sources such as gasoline engines, but many types of cancer cells also produce it naturally. Tumors can generate unusually large amounts of carbon monoxide, meaning that the gas could serve as a biological marker for identifying cancer cells.
Scientists at RIKEN’s Biofunctional Synthetic Chemistry Laboratory investigated whether this difference could be exploited. Their strategy involved delivering metal catalysts into cells and using the excess carbon monoxide inside cancer cells to trigger chemical reactions that produce toxic compounds. In principle, the reaction should occur mainly in cells containing sufficient carbon monoxide, while normal cells would be spared.
Protecting the catalyst inside cells
To build the system, the researchers used compounds known as palladacycles. These metal-containing compounds react with carbon monoxide to produce organic molecules called phenanthridinones. Some phenanthridinone derivatives are toxic to cells and have already been incorporated into anti-cancer drugs.
However, introducing a palladacycle directly into cells creates a significant problem. Glutathione and other substances can rapidly deactivate the palladium catalyst. Without an active catalyst, the reaction cannot produce the intended drug.
Tanaka’s team addressed this issue by building on earlier work involving metal catalysts in biological systems. The researchers encapsulated the palladacycle in albumin, a protein commonly found in blood. The protein carrier helps the complex travel through the bloodstream while shielding the palladium catalyst from substances that could deactivate it after it enters a cell.
Selective drug production in cancer cell cultures
The researchers first tested different palladacycles to identify the compound capable of producing the greatest amount of phenanthridinone.
They then exposed cultured human liver, cervical, breast and lung cancer cells to albumin–palladacycle complexes for 48 hours. The team also tested the compounds in non-cancerous cell lines to determine whether the same reactions occurred in healthy cells.
After 48 hours, the researchers detected phenanthridinone in the cancer cell lines but not in the normal cells. The result suggested that the albumin carrier had successfully protected the catalyst from glutathione and enabled the reaction to occur selectively in the cancer cells under the conditions tested.
The team subsequently refined the system so that the newly formed compounds could separate from the carrier and move freely inside cells. Further modifications enabled the reaction to produce particularly toxic phenanthridinone derivatives that are already used in anti-cancer drugs.
When the modified system was introduced into cultured liver cancer cells, the researchers observed the formation of anti-cancer compounds inside the cells. The cells then showed signs of damage associated with the toxic drug, providing evidence that the method can generate cancer-fighting substances directly at the intended target.
Why the drug did not form in blood
A major safety concern was whether carbon monoxide already present in the bloodstream could trigger the reaction before the compound reached cancer cells. If that happened, the resulting drug could damage blood cells instead of selectively affecting a tumor.
Laboratory tests showed that toxic drugs were not produced in the blood. The researchers believe this is because most carbon monoxide in the bloodstream is bound to hemoglobin, the protein responsible for transporting oxygen. In this bound form, the gas does not appear to be available for the reactions needed to manufacture the drug.
These findings suggest that the system may be able to travel through the bloodstream without producing harmful substances prematurely. However, additional research is needed to determine whether it is safe in living organisms.
“In our therapeutic strategy, molecules that are naturally present or produced in the body, including disease-related metabolites, are used as endogenous chemical raw materials to synthesize therapeutic molecules directly at the site of disease,” Tanaka says.
The researchers plan to move beyond cultured cells and test the approach in animal models. If those experiments are successful, the technology could contribute to a new class of cancer treatments that harness tumor chemistry to produce drugs at the disease site while limiting damage to healthy tissue.
Source: www.sciencedaily.com
