Pseudomonas Exotoxin A Based Toxins Targeting Epidermal Growth Factor Receptor for the Treatment of Prostate Cancer
The epidermal growth factor receptor (EGFR) was found to be a valuable target on prostate cancer (PCa) cells. However, EGFR inhibitors mostly failed in clinical studies with patients suffering from PCa. We therefore tested the targeted toxins EGF-PE40 and EGF-PE24mut consisting of the natural ligand...
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MDPI AG
2020-11-01
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| Series: | Toxins |
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| Online Access: | https://www.mdpi.com/2072-6651/12/12/753 |
| _version_ | 1827701219411361792 |
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| author | Alexandra Fischer Isis Wolf Hendrik Fuchs Anie Priscilla Masilamani Philipp Wolf |
| author_facet | Alexandra Fischer Isis Wolf Hendrik Fuchs Anie Priscilla Masilamani Philipp Wolf |
| author_sort | Alexandra Fischer |
| collection | DOAJ |
| description | The epidermal growth factor receptor (EGFR) was found to be a valuable target on prostate cancer (PCa) cells. However, EGFR inhibitors mostly failed in clinical studies with patients suffering from PCa. We therefore tested the targeted toxins EGF-PE40 and EGF-PE24mut consisting of the natural ligand EGF as binding domain and PE40, the natural toxin domain of <i>Pseudomonas</i> Exotoxin A, or PE24mut, the de-immunized variant thereof, as toxin domains. Both targeted toxins were expressed in the periplasm of <i>E.coli</i> and evoked an inhibition of protein biosynthesis in EGFR-expressing PCa cells. Concentration- and time-dependent killing of PCa cells was found with IC<sub>50</sub> values after 48 and 72 h in the low nanomolar or picomolar range based on the induction of apoptosis. EGF-PE24mut was found to be about 11- to 120-fold less toxic than EGF-PE40. Both targeted toxins were more than 600 to 140,000-fold more cytotoxic than the EGFR inhibitor erlotinib. Due to their high and specific cytotoxicity, the EGF-based targeted toxins EGF-PE40 and EGF-PE24mut represent promising candidates for the future treatment of PCa. |
| first_indexed | 2024-03-10T14:28:35Z |
| format | Article |
| id | doaj.art-dbe36a4df27345529f7e9f62b9f7773f |
| institution | Directory Open Access Journal |
| issn | 2072-6651 |
| language | English |
| last_indexed | 2024-03-10T14:28:35Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Toxins |
| spelling | doaj.art-dbe36a4df27345529f7e9f62b9f7773f2023-11-20T22:47:29ZengMDPI AGToxins2072-66512020-11-01121275310.3390/toxins12120753Pseudomonas Exotoxin A Based Toxins Targeting Epidermal Growth Factor Receptor for the Treatment of Prostate CancerAlexandra Fischer0Isis Wolf1Hendrik Fuchs2Anie Priscilla Masilamani3Philipp Wolf4Faculty of Medicine, University of Freiburg, 79106 Freiburg, GermanyFaculty of Medicine, University of Freiburg, 79106 Freiburg, GermanyInstitute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 13353 Berlin, GermanyFaculty of Medicine, University of Freiburg, 79106 Freiburg, GermanyFaculty of Medicine, University of Freiburg, 79106 Freiburg, GermanyThe epidermal growth factor receptor (EGFR) was found to be a valuable target on prostate cancer (PCa) cells. However, EGFR inhibitors mostly failed in clinical studies with patients suffering from PCa. We therefore tested the targeted toxins EGF-PE40 and EGF-PE24mut consisting of the natural ligand EGF as binding domain and PE40, the natural toxin domain of <i>Pseudomonas</i> Exotoxin A, or PE24mut, the de-immunized variant thereof, as toxin domains. Both targeted toxins were expressed in the periplasm of <i>E.coli</i> and evoked an inhibition of protein biosynthesis in EGFR-expressing PCa cells. Concentration- and time-dependent killing of PCa cells was found with IC<sub>50</sub> values after 48 and 72 h in the low nanomolar or picomolar range based on the induction of apoptosis. EGF-PE24mut was found to be about 11- to 120-fold less toxic than EGF-PE40. Both targeted toxins were more than 600 to 140,000-fold more cytotoxic than the EGFR inhibitor erlotinib. Due to their high and specific cytotoxicity, the EGF-based targeted toxins EGF-PE40 and EGF-PE24mut represent promising candidates for the future treatment of PCa.https://www.mdpi.com/2072-6651/12/12/753prostate cancertargeted toxinsepidermal growth factorepidermal growth factor receptor<i>Pseudomonas</i> Exotoxin A |
| spellingShingle | Alexandra Fischer Isis Wolf Hendrik Fuchs Anie Priscilla Masilamani Philipp Wolf Pseudomonas Exotoxin A Based Toxins Targeting Epidermal Growth Factor Receptor for the Treatment of Prostate Cancer Toxins prostate cancer targeted toxins epidermal growth factor epidermal growth factor receptor <i>Pseudomonas</i> Exotoxin A |
| title | Pseudomonas Exotoxin A Based Toxins Targeting Epidermal Growth Factor Receptor for the Treatment of Prostate Cancer |
| title_full | Pseudomonas Exotoxin A Based Toxins Targeting Epidermal Growth Factor Receptor for the Treatment of Prostate Cancer |
| title_fullStr | Pseudomonas Exotoxin A Based Toxins Targeting Epidermal Growth Factor Receptor for the Treatment of Prostate Cancer |
| title_full_unstemmed | Pseudomonas Exotoxin A Based Toxins Targeting Epidermal Growth Factor Receptor for the Treatment of Prostate Cancer |
| title_short | Pseudomonas Exotoxin A Based Toxins Targeting Epidermal Growth Factor Receptor for the Treatment of Prostate Cancer |
| title_sort | pseudomonas exotoxin a based toxins targeting epidermal growth factor receptor for the treatment of prostate cancer |
| topic | prostate cancer targeted toxins epidermal growth factor epidermal growth factor receptor <i>Pseudomonas</i> Exotoxin A |
| url | https://www.mdpi.com/2072-6651/12/12/753 |
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