Dissemin is shutting down on January 1st, 2025

Published in

National Academy of Sciences, Proceedings of the National Academy of Sciences, 26(117), p. 15182-15192, 2020

DOI: 10.1073/pnas.1922072117

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Uncoupling DNA damage from chromatin damage to detoxify doxorubicin

This paper was not found in any repository, but could be made available legally by the author.
This paper was not found in any repository, but could be made available legally by the author.

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Abstract

Significance Anthracyclines like doxorubicin are anticancer drugs, used by over 1 million cancer patients annually. However, they cause severe side effects, most notably, cardiotoxicity and therapy-related malignancies. It is unclear whether these side effects are directly linked to their anticancer activity. Doxorubicin exerts two activities: DNA damage and chromatin damage. Here, we show that both activities conspire in the cardiotoxicity, while doxorubicin variants with only chromatin-damaging activity remain active anticancer drugs devoid of side effects. This challenges the concept that doxorubicin works primarily by inducing DNA double-strand breaks and reveals another major anticancer activity, chromatin damage. Translating these observations will yield anticancer drugs for patients that are currently excluded from doxorubicin treatment and improve the quality of life of cancer survivors.