The many faces of doxorubicin and how to improve it for new cancer therapies

Anthracyclines like doxorubicin are still cornerstones in the treatment of a series of tumors. They should act by poisoning topoisomerase II causing DNA double stranded breaks. However, they also evict histones at defined sites in chromatin. We chemically separated these two activities to show that histone eviction was the most cytotoxic activity. Doxorubicin variants acting through histone eviction are active cancer drugs but have lost various toxic side effects including dose-dependent cardiotoxicity. These variants can still be used in the treatment of relapsed cancer patients and can strongly improve their overall survival. New activities in old cancer drugs can thus be explored to control toxicities, allow chronic treatment and improve the quality of life of cancer survivors.