The Flavin Reductase MsuE Is a Novel Nitroreductase that Can Efficiently Activate Two Promising Next-Generation Prodrugs for Gene-Directed Enzyme Prodrug Therapy
Bacterial nitroreductase enzymes that can efficiently catalyse the oxygen-independent reduction of prodrugs originally developed to target tumour hypoxia offer great potential for expanding the therapeutic range of these molecules to aerobic tumour regions, via the emerging cancer strategy of gene-d...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2013-08-01
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| Series: | Cancers |
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| Online Access: | http://www.mdpi.com/2072-6694/5/3/985 |
| _version_ | 1797716394473684992 |
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| author | David F. Ackerley Janine N. Copp Laura K. Green Mathew A. Storey Elsie M. Williams Jeff B. Smaill Adam V. Patterson |
| author_facet | David F. Ackerley Janine N. Copp Laura K. Green Mathew A. Storey Elsie M. Williams Jeff B. Smaill Adam V. Patterson |
| author_sort | David F. Ackerley |
| collection | DOAJ |
| description | Bacterial nitroreductase enzymes that can efficiently catalyse the oxygen-independent reduction of prodrugs originally developed to target tumour hypoxia offer great potential for expanding the therapeutic range of these molecules to aerobic tumour regions, via the emerging cancer strategy of gene-directed enzyme prodrug therapy (GDEPT). Two promising hypoxia prodrugs for GDEPT are the dinitrobenzamide mustard PR-104A, and the nitrochloromethylbenzindoline prodrug nitro-CBI-DEI. We describe here use of a nitro-quenched fluorogenic probe to identify MsuE from Pseudomonas aeruginosa as a novel nitroreductase candidate for GDEPT. In SOS and bacteria-delivered enzyme prodrug cytotoxicity assays MsuE was less effective at activating CB1954 (a first-generation GDEPT prodrug) than the “gold standard” nitroreductases NfsA and NfsB from Escherichia coli. However, MsuE exhibited comparable levels of activity with PR-104A and nitro-CBI-DEI, and is the first nitroreductase outside of the NfsA and NfsB enzyme families to do so. These in vitro findings suggest that MsuE is worthy of further evaluation in in vivo models of GDEPT. |
| first_indexed | 2024-03-12T08:20:48Z |
| format | Article |
| id | doaj.art-75ac209361c14329b19973e5b1f7084c |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T08:20:48Z |
| publishDate | 2013-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-75ac209361c14329b19973e5b1f7084c2023-09-02T18:29:21ZengMDPI AGCancers2072-66942013-08-015398599710.3390/cancers5030985The Flavin Reductase MsuE Is a Novel Nitroreductase that Can Efficiently Activate Two Promising Next-Generation Prodrugs for Gene-Directed Enzyme Prodrug TherapyDavid F. AckerleyJanine N. CoppLaura K. GreenMathew A. StoreyElsie M. WilliamsJeff B. SmaillAdam V. PattersonBacterial nitroreductase enzymes that can efficiently catalyse the oxygen-independent reduction of prodrugs originally developed to target tumour hypoxia offer great potential for expanding the therapeutic range of these molecules to aerobic tumour regions, via the emerging cancer strategy of gene-directed enzyme prodrug therapy (GDEPT). Two promising hypoxia prodrugs for GDEPT are the dinitrobenzamide mustard PR-104A, and the nitrochloromethylbenzindoline prodrug nitro-CBI-DEI. We describe here use of a nitro-quenched fluorogenic probe to identify MsuE from Pseudomonas aeruginosa as a novel nitroreductase candidate for GDEPT. In SOS and bacteria-delivered enzyme prodrug cytotoxicity assays MsuE was less effective at activating CB1954 (a first-generation GDEPT prodrug) than the “gold standard” nitroreductases NfsA and NfsB from Escherichia coli. However, MsuE exhibited comparable levels of activity with PR-104A and nitro-CBI-DEI, and is the first nitroreductase outside of the NfsA and NfsB enzyme families to do so. These in vitro findings suggest that MsuE is worthy of further evaluation in in vivo models of GDEPT.http://www.mdpi.com/2072-6694/5/3/985gene therapyGDEPTnitroaromatic prodrugnitroreductaseCB1954PR-104ANitro-CBI-DEISOS chromotest |
| spellingShingle | David F. Ackerley Janine N. Copp Laura K. Green Mathew A. Storey Elsie M. Williams Jeff B. Smaill Adam V. Patterson The Flavin Reductase MsuE Is a Novel Nitroreductase that Can Efficiently Activate Two Promising Next-Generation Prodrugs for Gene-Directed Enzyme Prodrug Therapy Cancers gene therapy GDEPT nitroaromatic prodrug nitroreductase CB1954 PR-104A Nitro-CBI-DEI SOS chromotest |
| title | The Flavin Reductase MsuE Is a Novel Nitroreductase that Can Efficiently Activate Two Promising Next-Generation Prodrugs for Gene-Directed Enzyme Prodrug Therapy |
| title_full | The Flavin Reductase MsuE Is a Novel Nitroreductase that Can Efficiently Activate Two Promising Next-Generation Prodrugs for Gene-Directed Enzyme Prodrug Therapy |
| title_fullStr | The Flavin Reductase MsuE Is a Novel Nitroreductase that Can Efficiently Activate Two Promising Next-Generation Prodrugs for Gene-Directed Enzyme Prodrug Therapy |
| title_full_unstemmed | The Flavin Reductase MsuE Is a Novel Nitroreductase that Can Efficiently Activate Two Promising Next-Generation Prodrugs for Gene-Directed Enzyme Prodrug Therapy |
| title_short | The Flavin Reductase MsuE Is a Novel Nitroreductase that Can Efficiently Activate Two Promising Next-Generation Prodrugs for Gene-Directed Enzyme Prodrug Therapy |
| title_sort | flavin reductase msue is a novel nitroreductase that can efficiently activate two promising next generation prodrugs for gene directed enzyme prodrug therapy |
| topic | gene therapy GDEPT nitroaromatic prodrug nitroreductase CB1954 PR-104A Nitro-CBI-DEI SOS chromotest |
| url | http://www.mdpi.com/2072-6694/5/3/985 |
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