Scientists have developed an experimental technique that uses carbon monoxide produced by cancer cells to create potential cancer-fighting compounds directly inside tumours. The approach could offer a new direction for targeted cancer treatment by helping limit damage to healthy cells.
The researchers developed an albumin-palladacycle complex (APC), a system that uses carbon monoxide (CO) naturally produced inside cells as a building block to create active drug compounds. It can also detect elevated CO levels, which are linked to certain metabolic changes in cancer cells.
Conventional chemotherapy can damage healthy tissues because drugs travel throughout the body, often causing side effects. While existing prodrug approaches aim to activate drugs in response to tumour-specific conditions, producing active compounds directly at the disease site could offer another way to improve targeting.
How Researchers Overcame A Key Challenge
Carrying out chemical reactions inside living cells is difficult. Palladium-based catalysts can drive these reactions, but glutathione (GSH), a natural antioxidant found in cells, can quickly deactivate the metal.
To address this, the researchers enclosed the palladium complexes in human serum albumin, a protein commonly used in drug delivery. A coumarin-based molecule helps guide the complex into a protective pocket within the protein, shielding the palladium from glutathione and helping cells absorb the system.
The researchers first tested whether the system could detect naturally produced CO and use it to form phenanthridinone derivatives, compounds associated with biological activities such as PARP and topoisomerase inhibition.
Experiments on human liver, cervical, breast and lung cancer cell lines showed detectable production of a phenanthridinone compound. Normal fibroblast cells produced substantially lower amounts, suggesting that differences in CO levels could help the system activate more selectively in cancer cells.
Tests Reveal Differences In Cancer And Normal Cells
The team then developed a system that could produce and release an active compound inside cells. It was used to synthesise an oxynitidine-derived phenanthridinone associated with topoisomerase I inhibition.
Tests in HepG2 liver cancer cells confirmed that the compound was produced inside the cells. The system recorded an IC50 value of 13.99 micromolar in these cancer cells, compared with 37.54 micromolar in normal fibroblasts, indicating a modest degree of selectivity.
Blocking heme oxygenase-1 (HO-1), an enzyme involved in CO production, reduced the system's cell-killing effect. This supports the role of naturally produced CO in activating the reaction. Further tests also showed a dose-dependent reduction in long-term colony formation in MCF7 breast cancer cells.
More Research Needed Before Human Trials
The experiments were conducted in cell cultures, alongside an ex vivo assessment of the system's stability in mouse blood. The technique has not yet been established as an effective treatment in living animals or humans.
Further studies will be needed to assess its safety and effectiveness and determine whether the approach could eventually be developed into a cancer treatment.
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