Tyrosyl-DNA Phosphodiesterase 1 and Topoisomerase I Activities as Predictive Indicators for Glioblastoma Susceptibility to Genotoxic Agents
Glioblastoma (GBM) patients have an estimated survival of ~15 months with treatment, and the standard of care only modestly enhances patient survival. Identifying biomarkers representing vulnerabilities may allow for the selection of efficacious chemotherapy options to address personalized variation...
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| Format: | Article |
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MDPI AG
2019-09-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/11/10/1416 |
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| author | Wenjie Wang Monica Rodriguez-Silva Arlet M. Acanda de la Rocha Aizik L. Wolf Yanhao Lai Yuan Liu William C. Reinhold Yves Pommier Jeremy W. Chambers Yuk-Ching Tse-Dinh |
| author_facet | Wenjie Wang Monica Rodriguez-Silva Arlet M. Acanda de la Rocha Aizik L. Wolf Yanhao Lai Yuan Liu William C. Reinhold Yves Pommier Jeremy W. Chambers Yuk-Ching Tse-Dinh |
| author_sort | Wenjie Wang |
| collection | DOAJ |
| description | Glioblastoma (GBM) patients have an estimated survival of ~15 months with treatment, and the standard of care only modestly enhances patient survival. Identifying biomarkers representing vulnerabilities may allow for the selection of efficacious chemotherapy options to address personalized variations in GBM tumors. Irinotecan targets topoisomerase I (TOP1) by forming a ternary DNA−TOP1 cleavage complex (TOP1cc), inducing apoptosis. Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a crucial repair enzyme that may reduce the effectiveness of irinotecan. We treated GBM cell lines with increasing concentrations of irinotecan and compared the IC<sub>50</sub> values. We found that the TDP1/TOP1 activity ratio had the strongest correlation (Pearson correlation coefficient R = 0.972, based on the average from three sets of experiments) with IC<sub>50</sub> values following irinotecan treatment. Increasing the TDP1/TOP1 activity ratio by the ectopic expression of wild-type TDP1 increased in irinotecan IC<sub>50</sub>, while the expression of the TDP1 catalytic-null mutant did not alter the susceptibility to irinotecan. The TDP1/TOP1 activity ratio may be a new predictive indicator for GBM vulnerability to irinotecan, allowing for the selection of individual patients for irinotecan treatment based on risk−benefit. Moreover, TDP1 inhibitors may be a novel combination treatment with irinotecan to improve GBM patient responsiveness to genotoxic chemotherapies. |
| first_indexed | 2024-03-12T06:34:31Z |
| format | Article |
| id | doaj.art-cea55c7fd8d747758aa75196939f7bb3 |
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| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T06:34:31Z |
| publishDate | 2019-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-cea55c7fd8d747758aa75196939f7bb32023-09-03T01:27:12ZengMDPI AGCancers2072-66942019-09-011110141610.3390/cancers11101416cancers11101416Tyrosyl-DNA Phosphodiesterase 1 and Topoisomerase I Activities as Predictive Indicators for Glioblastoma Susceptibility to Genotoxic AgentsWenjie Wang0Monica Rodriguez-Silva1Arlet M. Acanda de la Rocha2Aizik L. Wolf3Yanhao Lai4Yuan Liu5William C. Reinhold6Yves Pommier7Jeremy W. Chambers8Yuk-Ching Tse-Dinh9Biomolecular Sciences Institute, Florida International University, Miami, FL 33199, USADepartment of Environmental Health Sciences, Florida International University, Miami, FL 33199, USADepartment of Environmental Health Sciences, Florida International University, Miami, FL 33199, USADepartment of Neurosurgery, Miami Neuroscience Center at Larkin, South Miami, FL 33143, USABiomolecular Sciences Institute, Florida International University, Miami, FL 33199, USABiomolecular Sciences Institute, Florida International University, Miami, FL 33199, USADevelopmental Therapeutic Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 USADevelopmental Therapeutic Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 USABiomolecular Sciences Institute, Florida International University, Miami, FL 33199, USABiomolecular Sciences Institute, Florida International University, Miami, FL 33199, USAGlioblastoma (GBM) patients have an estimated survival of ~15 months with treatment, and the standard of care only modestly enhances patient survival. Identifying biomarkers representing vulnerabilities may allow for the selection of efficacious chemotherapy options to address personalized variations in GBM tumors. Irinotecan targets topoisomerase I (TOP1) by forming a ternary DNA−TOP1 cleavage complex (TOP1cc), inducing apoptosis. Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a crucial repair enzyme that may reduce the effectiveness of irinotecan. We treated GBM cell lines with increasing concentrations of irinotecan and compared the IC<sub>50</sub> values. We found that the TDP1/TOP1 activity ratio had the strongest correlation (Pearson correlation coefficient R = 0.972, based on the average from three sets of experiments) with IC<sub>50</sub> values following irinotecan treatment. Increasing the TDP1/TOP1 activity ratio by the ectopic expression of wild-type TDP1 increased in irinotecan IC<sub>50</sub>, while the expression of the TDP1 catalytic-null mutant did not alter the susceptibility to irinotecan. The TDP1/TOP1 activity ratio may be a new predictive indicator for GBM vulnerability to irinotecan, allowing for the selection of individual patients for irinotecan treatment based on risk−benefit. Moreover, TDP1 inhibitors may be a novel combination treatment with irinotecan to improve GBM patient responsiveness to genotoxic chemotherapies.https://www.mdpi.com/2072-6694/11/10/1416topoisomeraseTOP1TDP1irinotecanrisk-benefitpredictive indicator |
| spellingShingle | Wenjie Wang Monica Rodriguez-Silva Arlet M. Acanda de la Rocha Aizik L. Wolf Yanhao Lai Yuan Liu William C. Reinhold Yves Pommier Jeremy W. Chambers Yuk-Ching Tse-Dinh Tyrosyl-DNA Phosphodiesterase 1 and Topoisomerase I Activities as Predictive Indicators for Glioblastoma Susceptibility to Genotoxic Agents Cancers topoisomerase TOP1 TDP1 irinotecan risk-benefit predictive indicator |
| title | Tyrosyl-DNA Phosphodiesterase 1 and Topoisomerase I Activities as Predictive Indicators for Glioblastoma Susceptibility to Genotoxic Agents |
| title_full | Tyrosyl-DNA Phosphodiesterase 1 and Topoisomerase I Activities as Predictive Indicators for Glioblastoma Susceptibility to Genotoxic Agents |
| title_fullStr | Tyrosyl-DNA Phosphodiesterase 1 and Topoisomerase I Activities as Predictive Indicators for Glioblastoma Susceptibility to Genotoxic Agents |
| title_full_unstemmed | Tyrosyl-DNA Phosphodiesterase 1 and Topoisomerase I Activities as Predictive Indicators for Glioblastoma Susceptibility to Genotoxic Agents |
| title_short | Tyrosyl-DNA Phosphodiesterase 1 and Topoisomerase I Activities as Predictive Indicators for Glioblastoma Susceptibility to Genotoxic Agents |
| title_sort | tyrosyl dna phosphodiesterase 1 and topoisomerase i activities as predictive indicators for glioblastoma susceptibility to genotoxic agents |
| topic | topoisomerase TOP1 TDP1 irinotecan risk-benefit predictive indicator |
| url | https://www.mdpi.com/2072-6694/11/10/1416 |
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