A switching mechanism in doxorubicin bioactivation can be exploited to control doxorubicin toxicity.
Although doxorubicin toxicity in cancer cells is multifactorial, the enzymatic bioactivation of the drug can significantly contribute to its cytotoxicity. Previous research has identified most of the components that comprise the doxorubicin bioactivation network; however, adaptation of the network t...
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| Language: | English |
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Public Library of Science (PLoS)
2011-09-01
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| Series: | PLoS Computational Biology |
| Online Access: | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1002151&type=printable |
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| _version_ | 1850162288662675456 |
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| author | Nnenna A Finn Harry W Findley Melissa L Kemp |
| author_facet | Nnenna A Finn Harry W Findley Melissa L Kemp |
| author_sort | Nnenna A Finn |
| collection | DOAJ |
| description | Although doxorubicin toxicity in cancer cells is multifactorial, the enzymatic bioactivation of the drug can significantly contribute to its cytotoxicity. Previous research has identified most of the components that comprise the doxorubicin bioactivation network; however, adaptation of the network to changes in doxorubicin treatment or to patient-specific changes in network components is much less understood. To investigate the properties of the coupled reduction/oxidation reactions of the doxorubicin bioactivation network, we analyzed metabolic differences between two patient-derived acute lymphoblastic leukemia (ALL) cell lines exhibiting varied doxorubicin sensitivities. We developed computational models that accurately predicted doxorubicin bioactivation in both ALL cell lines at high and low doxorubicin concentrations. Oxygen-dependent redox cycling promoted superoxide accumulation while NADPH-dependent reductive conversion promoted semiquinone doxorubicin. This fundamental switch in control is observed between doxorubicin sensitive and insensitive ALL cells and between high and low doxorubicin concentrations. We demonstrate that pharmacological intervention strategies can be employed to either enhance or impede doxorubicin cytotoxicity in ALL cells due to the switching that occurs between oxygen-dependent superoxide generation and NADPH-dependent doxorubicin semiquinone formation. |
| format | Article |
| id | doaj-art-4a79f641b30f43fcafab5a33a756e689 |
| institution | OA Journals |
| issn | 1553-734X 1553-7358 |
| language | English |
| publishDate | 2011-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj-art-4a79f641b30f43fcafab5a33a756e6892025-08-20T02:22:37ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582011-09-0179e100215110.1371/journal.pcbi.1002151A switching mechanism in doxorubicin bioactivation can be exploited to control doxorubicin toxicity.Nnenna A FinnHarry W FindleyMelissa L KempAlthough doxorubicin toxicity in cancer cells is multifactorial, the enzymatic bioactivation of the drug can significantly contribute to its cytotoxicity. Previous research has identified most of the components that comprise the doxorubicin bioactivation network; however, adaptation of the network to changes in doxorubicin treatment or to patient-specific changes in network components is much less understood. To investigate the properties of the coupled reduction/oxidation reactions of the doxorubicin bioactivation network, we analyzed metabolic differences between two patient-derived acute lymphoblastic leukemia (ALL) cell lines exhibiting varied doxorubicin sensitivities. We developed computational models that accurately predicted doxorubicin bioactivation in both ALL cell lines at high and low doxorubicin concentrations. Oxygen-dependent redox cycling promoted superoxide accumulation while NADPH-dependent reductive conversion promoted semiquinone doxorubicin. This fundamental switch in control is observed between doxorubicin sensitive and insensitive ALL cells and between high and low doxorubicin concentrations. We demonstrate that pharmacological intervention strategies can be employed to either enhance or impede doxorubicin cytotoxicity in ALL cells due to the switching that occurs between oxygen-dependent superoxide generation and NADPH-dependent doxorubicin semiquinone formation.https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1002151&type=printable |
| spellingShingle | Nnenna A Finn Harry W Findley Melissa L Kemp A switching mechanism in doxorubicin bioactivation can be exploited to control doxorubicin toxicity. PLoS Computational Biology |
| title | A switching mechanism in doxorubicin bioactivation can be exploited to control doxorubicin toxicity. |
| title_full | A switching mechanism in doxorubicin bioactivation can be exploited to control doxorubicin toxicity. |
| title_fullStr | A switching mechanism in doxorubicin bioactivation can be exploited to control doxorubicin toxicity. |
| title_full_unstemmed | A switching mechanism in doxorubicin bioactivation can be exploited to control doxorubicin toxicity. |
| title_short | A switching mechanism in doxorubicin bioactivation can be exploited to control doxorubicin toxicity. |
| title_sort | switching mechanism in doxorubicin bioactivation can be exploited to control doxorubicin toxicity |
| url | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1002151&type=printable |
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