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Detoxifying doxorubicin

ABSTRACT: The anthracycline doxorubicin is a highly effective anti-cancer drug associated with severe side effects, including secondary tumors and cardiotoxicity. Doxorubicin induces DNA damage through double-strand breaks (DSBs) and epigenetic or chromatin damage through histone eviction. We examined whether separation of these activities can help to detoxify doxorubicin, while maintaining its chemotherapeutic efficacy. We show that anthracycline variants harboring the histone eviction activity alone remain potent anti-cancer drugs, while greatly alleviating cardiotoxicity and secondary tumor formation. We thus demonstrate that treatment-limited side effects of doxorubicin can be synthesized away, yielding effective chemotherapeutics towards improved and prolonged treatment responses and higher patient quality of life.

ORGANISM(S): Homo sapiens

PROVIDER: GSE108179 | GEO | 2019/09/01

REPOSITORIES: GEO

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Separating DNA from chromatin damage activities detoxifies the anti-cancer drug doxorubicin

Project description:The anthracycline doxorubicin (Doxo) is one of the most effective and commonly used anti-cancer drugs. However, its clinical application is limited by severe side effects, such as cardiotoxicity, therapy-related tumors and infertility. Doxo induces both DNA damage through double-strand breaks and chromatin damage through histone eviction. We examined whether separating these activities would detoxify Doxo, while maintaining its chemotherapeutic efficacy. Here we present anthracycline variants harboring the histone eviction activity alone which remain potent anti-cancer drugs, while greatly alleviating cardiotoxicity and therapy-related tumor formation. This suggests that the treatment-limited side effects of Doxo in mice can be strongly reduced by modifying the chemical structure. The modified anthracycline anti-cancer drugs may provide effective chemotherapeutics allowing prolonged treatment and a higher quality of life post-treatment.

2022-10-01 | GSE122143 | GEO

Genome-wide analysis of histone eviction by FAIRE-Seq

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Project description:Doxorubicin is a widely used and effective anthracycline chemotherapy drug. However, it causes cardiotoxicity and also a few negative effects on skeletal muscle as well. As a result, cancer treatment might actually worsen cancer-induced cachexia and consequently the prognosis of the disease. Inhibiting myostatin/activin signaling is known to increase muscle size. This pathway blockade by soluble activin receptor IIB (sAcvR2B-Fc) has also prolonged survival in cancer, even of animals in which tumor growth is not inhibited. It is not known, however, whether blocking this pathway affects chemotherapy-induced muscle wasting. We found that doxorubicin induces muscle atrophy which is prevented by a blocker for activin receptor 2B ligands (sAcvR2B-Fc).

2016-09-25 | GSE77745 | GEO

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