Anti-cancer drug more effective against tumors when combined with antirheumatic

Anti-cancer drugs are more effective against tumors if they are combined with an antirheumatic, a new study has shown.

According to scientists at EPFL and NTU, the synergistic effects of the anti-cancer drug and an antirheumatic improves the former’s ability to fight and kill cancer cells. The findings of the study are published in Natural Communications wherein scientists explored the synergistic effects of two unrelated drugs: auranofin (Ridaura), a gold-containing drug that is used to alleviate the symptoms of rheumatoid arthritis, and RAPTA-T, a ruthenium-containing anticancer drug that disrupts both tumor growth and metastasis.

The two drugs are used in completely different conditions but studies have recently indicated that auranofin acts against cancer. Scientists determined that drugs do not only bind a single site on a specific molecule, but can also bind and affect other, unrelated sites — either on the same molecule or on a different one. For example, a drug that is meant to bind and activate a receptor could also bind and block an enzyme. This off-site activity frequently gives rise to drug side effects, but separate drug-binding sites can also work together synergistically in a productive fashion.

Scientists specifically explored the synergistic effects of the two drugs on packaged DNA inside cancer cells. Despite popular depictions, the long strands of DNA in the cell spend most of their time tightly wound around specialized proteins called histones. Whenever a particular sequence, e.g. a gene, is needed, that section of DNA is unwound and read by the appropriate biological machinery.

Allosteric Binding of Auranofin and RAPTA-T on a Nucleosome
Allosteric Binding of Auranofin and RAPTA-T on a Nucleosome

The study found that combining the two drugs had an increased effect of killing of cancer cells, while individually, the drugs have considerably less impact on cell viability. When RAPTA-T is given, it forms what are known as “adducts” with the histone proteins that package DNA. These adducts disrupt the normal function of DNA and cause the cell to die. In contrast, auranofin is much less prone to form adducts with the histone proteins, unless the two drugs are used together.

The researchers found that the binding of auranofin takes place through an allosteric, “action-over-a-distance” mechanism within the nucleosome, which is the component that contains the cell’s packaged DNA. Here, the researchers discovered that RAPTA-T helps the other drug’s ability to form histone adducts by binding on distant histone sites.

The authors conclude that this newly discovered allosteric mechanism “suggests that allosteric modulation in nucleosomes may have biological relevance and potential for therapeutic interventions.”

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