The combination of 2 unrelated drugs, RAPTA-T and auranofin, results in synergistic effects that improve the ability of RAPTA-T to kill tumors in a cell culture model of cancer, according to a study published in Nature Communications.1
RAPTA-T is a ruthenium anticancer drug that inhibits metastasis and tumorigenesis. Auranofin is a gold-complex drug used to treat rheumatoid arthritis.
Drugs can often bind multiple sites and locations besides their targets. Off-site binding can sometimes enable drugs to function synergistically together.
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This study revealed synergy between RAPTA-T and auranofin that is moderated by allosteric exchanges in chromatin. When the drugs were administered together, aurafonin was able to make formations called adducts with the chromatin to cause damage to the cancerous cell’s DNA. This damage resulted in increased death of tumor cells.
When these drugs were administered individually, neither was able to kill cancerous cells as well, and auranofin was unable to form adducts with the chromatin.
This chromatin-based allosteric synergy suggests epigenetic targeting could result in novel, effective therapeutic interventions in the treatment of cancer.
“The allosteric mechanism mediating drug–drug synergy we have characterized in this work suggests that there is untapped potential for therapeutic modulation of chromatin activity through exploitation of structural and dynamical features of the nucleosome,” the authors reported.
“Although we have made the initial discovery here with metal-based drugs, which are especially favourable for structural visualization and cellular tracking, it is likely that synergies and allosteric actions in the nucleosome occur with other drug classes as well.”
Reference
1. Adhireksan Z, Palermo G, Riedel T, et al. Allosteric cross-talk in chromatin can mediate drug-drug synergy. Nat Commun. 2017 Mar 30. doi: 10.1038/ncomms14860.
