.
‘Auranofin (anti-rheumatic drug) combined with RAPTA-T (anti-cancer drug) produces a synergistic effect and improves treatment against tumors.’
Studying the
Synergistic Effect of Two Unrelated Drugs
The 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.
Study Findings
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.
To conclude, the authors
suggest that the newly discovered mechanism may open up new possibilities of
treating tumors.
Drug-Drug Synergy
Synergism 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.
References :- 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
Source: Medindia
