Combining chemotherapeutic agents and netrin‐1 interference potentiates cancer cell death
Abstract The secreted factor netrin‐1 is upregulated in a fraction of human cancers as a mechanism to block apoptosis induced by netrin‐1 dependence receptors DCC and UNC5H. Targeted therapies aiming to trigger tumour cell death via netrin‐1/receptors interaction interference are under preclinical e...
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| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2013-10-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.1002/emmm.201302654 |
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| author | Andrea Paradisi Marion Creveaux Benjamin Gibert Guillaume Devailly Emeline Redoulez David Neves Elsa Cleyssac Isabelle Treilleux Christian Klein Gerhard Niederfellner Philippe A. Cassier Agnès Bernet Patrick Mehlen |
| author_facet | Andrea Paradisi Marion Creveaux Benjamin Gibert Guillaume Devailly Emeline Redoulez David Neves Elsa Cleyssac Isabelle Treilleux Christian Klein Gerhard Niederfellner Philippe A. Cassier Agnès Bernet Patrick Mehlen |
| author_sort | Andrea Paradisi |
| collection | DOAJ |
| description | Abstract The secreted factor netrin‐1 is upregulated in a fraction of human cancers as a mechanism to block apoptosis induced by netrin‐1 dependence receptors DCC and UNC5H. Targeted therapies aiming to trigger tumour cell death via netrin‐1/receptors interaction interference are under preclinical evaluation. We show here that Doxorubicin, 5‐Fluorouracil, Paclitaxel and Cisplatin treatments trigger, in various human cancer cell lines, an increase of netrin‐1 expression which is accompanied by netrin‐1 receptors increase. This netrin‐1 upregulation which appears to be p53‐dependent is a survival mechanism as netrin‐1 silencing by siRNA is associated with a potentiation of cancer cell death upon Doxorubicin treatment. We show that candidate drugs interfering with netrin‐1/netrin‐1 receptors interactions potentiate Doxorubicin, Cisplatin or 5‐Fluorouracil‐induced cancer cell death in vitro. Moreover, in a model of xenografted nude mice, we show that systemic Doxorubicin treatment triggers netrin‐1 upregulation in the tumour but not in normal organs, enhancing and prolonging tumour growth inhibiting effect of a netrin‐1 interfering drug. Together these data suggest that combining conventional chemotherapies with netrin‐1 interference could be a promising therapeutic approach. |
| format | Article |
| id | doaj-art-9e1bf643b90540ad9b57b1bd4832139a |
| institution | OA Journals |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2013-10-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-9e1bf643b90540ad9b57b1bd4832139a2025-08-20T02:11:22ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842013-10-015121821183410.1002/emmm.201302654Combining chemotherapeutic agents and netrin‐1 interference potentiates cancer cell deathAndrea Paradisi0Marion Creveaux1Benjamin Gibert2Guillaume Devailly3Emeline Redoulez4David Neves5Elsa Cleyssac6Isabelle Treilleux7Christian Klein8Gerhard Niederfellner9Philippe A. Cassier10Agnès Bernet11Patrick Mehlen12Apoptosis, Cancer and Development Laboratory – Equipe labellisée ‘La Ligue’, LabEx DEVweCAN, Centre de Cancérologie de Lyon, INSERM U1052‐CNRS UMR5286, Université de Lyon, Centre Léon BérardApoptosis, Cancer and Development Laboratory – Equipe labellisée ‘La Ligue’, LabEx DEVweCAN, Centre de Cancérologie de Lyon, INSERM U1052‐CNRS UMR5286, Université de Lyon, Centre Léon BérardApoptosis, Cancer and Development Laboratory – Equipe labellisée ‘La Ligue’, LabEx DEVweCAN, Centre de Cancérologie de Lyon, INSERM U1052‐CNRS UMR5286, Université de Lyon, Centre Léon BérardApoptosis, Cancer and Development Laboratory – Equipe labellisée ‘La Ligue’, LabEx DEVweCAN, Centre de Cancérologie de Lyon, INSERM U1052‐CNRS UMR5286, Université de Lyon, Centre Léon BérardApoptosis, Cancer and Development Laboratory – Equipe labellisée ‘La Ligue’, LabEx DEVweCAN, Centre de Cancérologie de Lyon, INSERM U1052‐CNRS UMR5286, Université de Lyon, Centre Léon BérardNetris PharmaNetris PharmaBiopathology Department, Centre Léon BérardDiscovery Oncology Roche Diagnostics GmbHDiscovery Oncology Roche Diagnostics GmbHApoptosis, Cancer and Development Laboratory – Equipe labellisée ‘La Ligue’, LabEx DEVweCAN, Centre de Cancérologie de Lyon, INSERM U1052‐CNRS UMR5286, Université de Lyon, Centre Léon BérardApoptosis, Cancer and Development Laboratory – Equipe labellisée ‘La Ligue’, LabEx DEVweCAN, Centre de Cancérologie de Lyon, INSERM U1052‐CNRS UMR5286, Université de Lyon, Centre Léon BérardApoptosis, Cancer and Development Laboratory – Equipe labellisée ‘La Ligue’, LabEx DEVweCAN, Centre de Cancérologie de Lyon, INSERM U1052‐CNRS UMR5286, Université de Lyon, Centre Léon BérardAbstract The secreted factor netrin‐1 is upregulated in a fraction of human cancers as a mechanism to block apoptosis induced by netrin‐1 dependence receptors DCC and UNC5H. Targeted therapies aiming to trigger tumour cell death via netrin‐1/receptors interaction interference are under preclinical evaluation. We show here that Doxorubicin, 5‐Fluorouracil, Paclitaxel and Cisplatin treatments trigger, in various human cancer cell lines, an increase of netrin‐1 expression which is accompanied by netrin‐1 receptors increase. This netrin‐1 upregulation which appears to be p53‐dependent is a survival mechanism as netrin‐1 silencing by siRNA is associated with a potentiation of cancer cell death upon Doxorubicin treatment. We show that candidate drugs interfering with netrin‐1/netrin‐1 receptors interactions potentiate Doxorubicin, Cisplatin or 5‐Fluorouracil‐induced cancer cell death in vitro. Moreover, in a model of xenografted nude mice, we show that systemic Doxorubicin treatment triggers netrin‐1 upregulation in the tumour but not in normal organs, enhancing and prolonging tumour growth inhibiting effect of a netrin‐1 interfering drug. Together these data suggest that combining conventional chemotherapies with netrin‐1 interference could be a promising therapeutic approach.https://doi.org/10.1002/emmm.201302654cancer therapyDCCdependence receptornetrin‐1, p53 |
| spellingShingle | Andrea Paradisi Marion Creveaux Benjamin Gibert Guillaume Devailly Emeline Redoulez David Neves Elsa Cleyssac Isabelle Treilleux Christian Klein Gerhard Niederfellner Philippe A. Cassier Agnès Bernet Patrick Mehlen Combining chemotherapeutic agents and netrin‐1 interference potentiates cancer cell death EMBO Molecular Medicine cancer therapy DCC dependence receptor netrin‐1, p53 |
| title | Combining chemotherapeutic agents and netrin‐1 interference potentiates cancer cell death |
| title_full | Combining chemotherapeutic agents and netrin‐1 interference potentiates cancer cell death |
| title_fullStr | Combining chemotherapeutic agents and netrin‐1 interference potentiates cancer cell death |
| title_full_unstemmed | Combining chemotherapeutic agents and netrin‐1 interference potentiates cancer cell death |
| title_short | Combining chemotherapeutic agents and netrin‐1 interference potentiates cancer cell death |
| title_sort | combining chemotherapeutic agents and netrin 1 interference potentiates cancer cell death |
| topic | cancer therapy DCC dependence receptor netrin‐1, p53 |
| url | https://doi.org/10.1002/emmm.201302654 |
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