- Synergism or interaction between two or more drugs can facilitate or increase the action of one drug by another.
- Scientists uncover that combining an anti-cancer drug along with an anti-rheumatic drug can produce a synergistic effect.
- A combination of Auranofin (anti-rheumatic drug) together with RAPTA-T (anti-cancer drug) could boost the killing of cancer cells.
The research study opens a new path to study the synergistic effect of an anti-cancer drug along with an anti-rheumatic drug. The synergistic effect created enhances the ability of the anti-cancer drug to kill cancer cells.
The research study was published in the journal Nature Communications.
Studying the Synergistic Effect of Two Unrelated DrugsThe study conducted in the lab of Paul Dyson and Ursula Rothlisberger at EPFL along with the lab of Curtis Davey at Nanyang Technological University, was instrumental in finding the synergistic effect of two unrelated drugs namely Auranofin (anti-rheumatic drug) and RAPTA-T (anti-cancer drug).
Auranofin is a gold-containing drug that provides relief against the symptoms of rheumatoid arthritis, and RAPTA-T is a ruthenium containing anti-cancer drug which can disrupt tumor growth and cancer spread (metastasis). RAPTA-T also reduces the side effects of chemotherapy because of its low toxicity.
Even though the two drugs are unrelated and used for different conditions, the idea of using them together arose because scientists have now found anticancer activity in auranofin. Drugs do not necessarily have to bind to a single site on a single molecule; they are capable of binding to unrelated sites either on the same molecule or a different one.
Thus, a drug which acts by binding to a receptor can also bind to another site and block the activity of an enzyme. This activity may result in frequent side-effects or the separate drug-binding sites can work together synergistically.
The research team observed the synergistic effects of the two drugs on packaged DNA inside the cancer cells. DNA inside cells is mostly in a packaged form where it is wound around specialized proteins called histones. A segment of DNA wound around eight histone proteins is called a nucleosome.
During the need of a particular sequence eg., a gene, the section of the DNA is unwound and read by the biological machinery.
The findings revealed that combining the two drugs
- Increased the effect of killing the cancer cells, than when taken individually; when taken separately they have a lesser impact on the cell viability.
- RAPTA-T, an anti-cancer drug may form 'adducts' (a product formed by the addition of two or more molecules) along with histone proteins that pack the DNA. These adducts kill the cancer cells.
- Auranofin is less capable of forming adducts individually and requires the addition of another compound.
- The binding of Auranofin takes place through an allosteric, "action-over-a-distance" mechanism within the nucleosome.
- The histone adducts of RAPTA-T may help the other drug's ability to form histone adducts at a distant histone site.
Drug-Drug SynergySynergism effect involves the interaction between two or more drugs, where the action of one drug is either facilitated or increased by another drug.
The effect can be either beneficial or harmful.
Synergistic effects may be
- Additive - The addition of two drugs together produces an overall increased effect.
- Supraadditive - The effect of the combination is greater than the individual effect of each drug.
- Zenita Adhireksan, Giulia Palermo, Tina Riedel, Zhujun Ma, Reyhan Muhammad, Ursula Rothlisberger, Paul J. Dyson, Curt A. Davey. Allosteric cross-talk in chromatin can mediate drug-drug synergy. Nature Communications 30 March 2017. DOI: 10.1038/ncomms14860
- K.D. Tripathi, Essentials of Medical Pharmacology, 6th Edition