New insights into the activities and toxicities of the old anticancer drug doxorubicin

The anthracycline drug doxorubicin is an effective anticancer drugs with both DNA‐ and chromatin‐damaging activity. While the chromatin‐damaging activity constitutes major anticancer efficacy of doxorubicin, combination with the DNA‐damaging activity plagues the drug with long‐term toxicities such a...

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Bibliographic Details
Published inThe FEBS journal Vol. 288; no. 21; pp. 6095 - 6111
Main Authors van der Zanden, Sabina Y., Qiao, Xiaohang, Neefjes, Jacques
Format Journal Article
LanguageEnglish
Published Oxford Blackwell Publishing Ltd 01.11.2021
John Wiley and Sons Inc
Subjects
aclarubicin
Anthracycline
anthracyclines
Anticancer properties
Antitumor agents
Cancer
Cardiotoxicity
Chemical separation
Chromatin
chromatin damage
Damage
Deoxyribonucleic acid
DNA
DNA damage
DNA topoisomerase (ATP-hydrolysing)
Doxorubicin
genome
Genomes
histone eviction
Histones
Quality of life
separation
Side effects
Solid tumors
State‐of‐the‐Art Review
State‐of‐the‐Art Reviews
therapy‐related tumours
topoisomerase II
Toxicity
Tumors
Online AccessGet full text

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Abstract The anthracycline drug doxorubicin is an effective anticancer drugs with both DNA‐ and chromatin‐damaging activity. While the chromatin‐damaging activity constitutes major anticancer efficacy of doxorubicin, combination with the DNA‐damaging activity plagues the drug with long‐term toxicities such as cardiotoxicity, therapy‐related malignancies and gonadotoxicity. Therefore, developing DNA damage‐free anthracyclines is a promising direction for novel treatment options with limited side effects, which has been shown to be possible. The anthracycline drug doxorubicin is among the most used—and useful—chemotherapeutics. While doxorubicin is highly effective in the treatment of various hematopoietic malignancies and solid tumours, its application is limited by severe adverse effects, including irreversible cardiotoxicity, therapy‐related malignancies and gonadotoxicity. This continues to motivate investigation into the mechanisms of anthracycline activities and toxicities, with the aim to overcome the latter without sacrificing the former. It has long been appreciated that doxorubicin causes DNA double‐strand breaks due to poisoning topoisomerase II. More recently, it became clear that doxorubicin also leads to chromatin damage achieved through eviction of histones from select sites in the genome. Evaluation of these activities in various anthracycline analogues has revealed that chromatin damage makes a major contribution to the efficacy of anthracycline drugs. Furthermore, the DNA‐damaging effect conspires with chromatin damage to cause a number of adverse effects. Structure–activity relationships within the anthracycline family offer opportunities for chemical separation of these activities towards development of effective analogues with limited adverse effects. In this review, we elaborate on our current understanding of the different activities of doxorubicin and their contributions to drug efficacy and side effects. We then offer our perspective on how the activities of this old anticancer drug can be amended in new ways to benefit cancer patients, by providing effective treatment with improved quality of life.
AbstractList The anthracycline drug doxorubicin is among the most used—and useful—chemotherapeutics. While doxorubicin is highly effective in the treatment of various hematopoietic malignancies and solid tumours, its application is limited by severe adverse effects, including irreversible cardiotoxicity, therapy‐related malignancies and gonadotoxicity. This continues to motivate investigation into the mechanisms of anthracycline activities and toxicities, with the aim to overcome the latter without sacrificing the former. It has long been appreciated that doxorubicin causes DNA double‐strand breaks due to poisoning topoisomerase II. More recently, it became clear that doxorubicin also leads to chromatin damage achieved through eviction of histones from select sites in the genome. Evaluation of these activities in various anthracycline analogues has revealed that chromatin damage makes a major contribution to the efficacy of anthracycline drugs. Furthermore, the DNA‐damaging effect conspires with chromatin damage to cause a number of adverse effects. Structure–activity relationships within the anthracycline family offer opportunities for chemical separation of these activities towards development of effective analogues with limited adverse effects. In this review, we elaborate on our current understanding of the different activities of doxorubicin and their contributions to drug efficacy and side effects. We then offer our perspective on how the activities of this old anticancer drug can be amended in new ways to benefit cancer patients, by providing effective treatment with improved quality of life.
The anthracycline drug doxorubicin is among the most used-and useful-chemotherapeutics. While doxorubicin is highly effective in the treatment of various hematopoietic malignancies and solid tumours, its application is limited by severe adverse effects, including irreversible cardiotoxicity, therapy-related malignancies and gonadotoxicity. This continues to motivate investigation into the mechanisms of anthracycline activities and toxicities, with the aim to overcome the latter without sacrificing the former. It has long been appreciated that doxorubicin causes DNA double-strand breaks due to poisoning topoisomerase II. More recently, it became clear that doxorubicin also leads to chromatin damage achieved through eviction of histones from select sites in the genome. Evaluation of these activities in various anthracycline analogues has revealed that chromatin damage makes a major contribution to the efficacy of anthracycline drugs. Furthermore, the DNA-damaging effect conspires with chromatin damage to cause a number of adverse effects. Structure-activity relationships within the anthracycline family offer opportunities for chemical separation of these activities towards development of effective analogues with limited adverse effects. In this review, we elaborate on our current understanding of the different activities of doxorubicin and their contributions to drug efficacy and side effects. We then offer our perspective on how the activities of this old anticancer drug can be amended in new ways to benefit cancer patients, by providing effective treatment with improved quality of life.The anthracycline drug doxorubicin is among the most used-and useful-chemotherapeutics. While doxorubicin is highly effective in the treatment of various hematopoietic malignancies and solid tumours, its application is limited by severe adverse effects, including irreversible cardiotoxicity, therapy-related malignancies and gonadotoxicity. This continues to motivate investigation into the mechanisms of anthracycline activities and toxicities, with the aim to overcome the latter without sacrificing the former. It has long been appreciated that doxorubicin causes DNA double-strand breaks due to poisoning topoisomerase II. More recently, it became clear that doxorubicin also leads to chromatin damage achieved through eviction of histones from select sites in the genome. Evaluation of these activities in various anthracycline analogues has revealed that chromatin damage makes a major contribution to the efficacy of anthracycline drugs. Furthermore, the DNA-damaging effect conspires with chromatin damage to cause a number of adverse effects. Structure-activity relationships within the anthracycline family offer opportunities for chemical separation of these activities towards development of effective analogues with limited adverse effects. In this review, we elaborate on our current understanding of the different activities of doxorubicin and their contributions to drug efficacy and side effects. We then offer our perspective on how the activities of this old anticancer drug can be amended in new ways to benefit cancer patients, by providing effective treatment with improved quality of life.
The anthracycline drug doxorubicin is an effective anticancer drugs with both DNA‐ and chromatin‐damaging activity. While the chromatin‐damaging activity constitutes major anticancer efficacy of doxorubicin, combination with the DNA‐damaging activity plagues the drug with long‐term toxicities such as cardiotoxicity, therapy‐related malignancies and gonadotoxicity. Therefore, developing DNA damage‐free anthracyclines is a promising direction for novel treatment options with limited side effects, which has been shown to be possible. The anthracycline drug doxorubicin is among the most used—and useful—chemotherapeutics. While doxorubicin is highly effective in the treatment of various hematopoietic malignancies and solid tumours, its application is limited by severe adverse effects, including irreversible cardiotoxicity, therapy‐related malignancies and gonadotoxicity. This continues to motivate investigation into the mechanisms of anthracycline activities and toxicities, with the aim to overcome the latter without sacrificing the former. It has long been appreciated that doxorubicin causes DNA double‐strand breaks due to poisoning topoisomerase II. More recently, it became clear that doxorubicin also leads to chromatin damage achieved through eviction of histones from select sites in the genome. Evaluation of these activities in various anthracycline analogues has revealed that chromatin damage makes a major contribution to the efficacy of anthracycline drugs. Furthermore, the DNA‐damaging effect conspires with chromatin damage to cause a number of adverse effects. Structure–activity relationships within the anthracycline family offer opportunities for chemical separation of these activities towards development of effective analogues with limited adverse effects. In this review, we elaborate on our current understanding of the different activities of doxorubicin and their contributions to drug efficacy and side effects. We then offer our perspective on how the activities of this old anticancer drug can be amended in new ways to benefit cancer patients, by providing effective treatment with improved quality of life.
Author Neefjes, Jacques
van der Zanden, Sabina Y.
Qiao, Xiaohang
AuthorAffiliation 3 Department of Head and Neck Oncology and Surgery The Netherlands Cancer Institute Amsterdam The Netherlands
1 Department of Cell and Chemical Biology ONCODE Institute Leiden University Medical Centre LUMC The Netherlands
2 Division of Tumour Biology and Immunology The Netherlands Cancer Institute Amsterdam The Netherlands
AuthorAffiliation_xml – name: 3 Department of Head and Neck Oncology and Surgery The Netherlands Cancer Institute Amsterdam The Netherlands
– name: 2 Division of Tumour Biology and Immunology The Netherlands Cancer Institute Amsterdam The Netherlands
– name: 1 Department of Cell and Chemical Biology ONCODE Institute Leiden University Medical Centre LUMC The Netherlands
Author_xml – sequence: 1
  givenname: Sabina Y.
  orcidid: 0000-0001-5587-1514
  surname: van der Zanden
  fullname: van der Zanden, Sabina Y.
  organization: Leiden University Medical Centre LUMC
– sequence: 2
  givenname: Xiaohang
  orcidid: 0000-0002-8690-4179
  surname: Qiao
  fullname: Qiao, Xiaohang
  organization: The Netherlands Cancer Institute
– sequence: 3
  givenname: Jacques
  orcidid: 0000-0001-6763-2211
  surname: Neefjes
  fullname: Neefjes, Jacques
  email: j.j.c.neefjes@lumc.nl
  organization: Leiden University Medical Centre LUMC
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Sabina Y. van der Zanden and Xiaohang Qiao contributed equally to this work.
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Snippet The anthracycline drug doxorubicin is an effective anticancer drugs with both DNA‐ and chromatin‐damaging activity. While the chromatin‐damaging activity...
The anthracycline drug doxorubicin is among the most used—and useful—chemotherapeutics. While doxorubicin is highly effective in the treatment of various...
The anthracycline drug doxorubicin is among the most used-and useful-chemotherapeutics. While doxorubicin is highly effective in the treatment of various...
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SubjectTerms aclarubicin
Anthracycline
anthracyclines
Anticancer properties
Antitumor agents
Cancer
Cardiotoxicity
Chemical separation
Chromatin
chromatin damage
Damage
Deoxyribonucleic acid
DNA
DNA damage
DNA topoisomerase (ATP-hydrolysing)
Doxorubicin
genome
Genomes
histone eviction
Histones
Quality of life
separation
Side effects
Solid tumors
State‐of‐the‐Art Review
State‐of‐the‐Art Reviews
therapy‐related tumours
topoisomerase II
Toxicity
Tumors
Title New insights into the activities and toxicities of the old anticancer drug doxorubicin
URI https://onlinelibrary.wiley.com/doi/abs/10.1111%2Ffebs.15583
https://www.proquest.com/docview/2589855618
https://www.proquest.com/docview/2449179940
https://www.proquest.com/docview/2636476856
https://pubmed.ncbi.nlm.nih.gov/PMC8597086
Volume 288
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