Repurposing of the Antiepileptic Drug Levetiracetam to Restrain Neuroendocrine Prostate Cancer and Inhibit Mast Cell Support to Adenocarcinoma
A relevant fraction of castration-resistant prostate cancers (CRPC) evolve into fatal neuroendocrine (NEPC) tumors in resistance to androgen deprivation and/or inhibitors of androgen receptor pathway. Therefore, effective drugs against both CRPC and NEPC are needed. We have previously described a du...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.622001/full |
| _version_ | 1819178891572412416 |
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| author | Roberta Sulsenti Barbara Frossi Lucia Bongiovanni Valeria Cancila Paola Ostano Irene Fischetti Claudia Enriquez Francesca Guana Giovanna Chiorino Claudio Tripodo Carlo E. Pucillo Mario P. Colombo Elena Jachetti |
| author_facet | Roberta Sulsenti Barbara Frossi Lucia Bongiovanni Valeria Cancila Paola Ostano Irene Fischetti Claudia Enriquez Francesca Guana Giovanna Chiorino Claudio Tripodo Carlo E. Pucillo Mario P. Colombo Elena Jachetti |
| author_sort | Roberta Sulsenti |
| collection | DOAJ |
| description | A relevant fraction of castration-resistant prostate cancers (CRPC) evolve into fatal neuroendocrine (NEPC) tumors in resistance to androgen deprivation and/or inhibitors of androgen receptor pathway. Therefore, effective drugs against both CRPC and NEPC are needed. We have previously described a dual role of mast cells (MCs) in prostate cancer, being capable to promote adenocarcinoma but also to restrain NEPC. This finding suggests that a molecule targeting both MCs and NEPC cells could be effective against prostate cancer. Using an in silico drug repurposing approach, here we identify the antiepileptic drug levetiracetam as a potential candidate for this purpose. We found that the protein target of levetiracetam, SV2A, is highly expressed by both NEPC cells and MCs infiltrating prostate adenocarcinoma, while it is low or negligible in adenocarcinoma cells. In vitro, levetiracetam inhibited the proliferation of NEPC cells and the degranulation of MCs. In mice bearing subcutaneous tumors levetiracetam was partially active on both NEPC and adenocarcinoma, the latter effect due to the inhibition of MMP9 release by MCs. Notably, in TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice subjected to surgical castration to mimic androgen deprivation therapy, levetiracetam reduced onset and frequency of both high grade prostatic intraepithelial neoplasia, adenocarcinoma and NEPC, thus increasing the number of cured mice showing only signs of tumor regression. Our results demonstrate that levetiracetam can directly restrain NEPC development after androgen deprivation, and that it can also block adenocarcinoma progression through the inhibition of some MCs functions. These findings open the possibility of further testing levetiracetam for the therapy of prostate cancer or of MC-mediated diseases. |
| first_indexed | 2024-12-22T21:49:45Z |
| format | Article |
| id | doaj.art-0e01c40f4e1447ddb6c588360cb31915 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-22T21:49:45Z |
| publishDate | 2021-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-0e01c40f4e1447ddb6c588360cb319152022-12-21T18:11:24ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-03-011210.3389/fimmu.2021.622001622001Repurposing of the Antiepileptic Drug Levetiracetam to Restrain Neuroendocrine Prostate Cancer and Inhibit Mast Cell Support to AdenocarcinomaRoberta Sulsenti0Barbara Frossi1Lucia Bongiovanni2Valeria Cancila3Paola Ostano4Irene Fischetti5Claudia Enriquez6Francesca Guana7Giovanna Chiorino8Claudio Tripodo9Carlo E. Pucillo10Mario P. Colombo11Elena Jachetti12Molecular Immunology Unit, Department of Research, Fondazione Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, ItalyImmunology Section, Department of Medicine, University of Udine, Udine, ItalyTumor Immunology Unit, Department of Health Sciences, University of Palermo, Palermo, ItalyTumor Immunology Unit, Department of Health Sciences, University of Palermo, Palermo, ItalyLaboratory of Cancer Genomics, Fondazione Edo ed Elvo Tempia, Biella, ItalyMolecular Immunology Unit, Department of Research, Fondazione Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, ItalyMolecular Immunology Unit, Department of Research, Fondazione Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, ItalyLaboratory of Cancer Genomics, Fondazione Edo ed Elvo Tempia, Biella, ItalyLaboratory of Cancer Genomics, Fondazione Edo ed Elvo Tempia, Biella, ItalyTumor Immunology Unit, Department of Health Sciences, University of Palermo, Palermo, ItalyImmunology Section, Department of Medicine, University of Udine, Udine, ItalyMolecular Immunology Unit, Department of Research, Fondazione Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, ItalyMolecular Immunology Unit, Department of Research, Fondazione Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milan, ItalyA relevant fraction of castration-resistant prostate cancers (CRPC) evolve into fatal neuroendocrine (NEPC) tumors in resistance to androgen deprivation and/or inhibitors of androgen receptor pathway. Therefore, effective drugs against both CRPC and NEPC are needed. We have previously described a dual role of mast cells (MCs) in prostate cancer, being capable to promote adenocarcinoma but also to restrain NEPC. This finding suggests that a molecule targeting both MCs and NEPC cells could be effective against prostate cancer. Using an in silico drug repurposing approach, here we identify the antiepileptic drug levetiracetam as a potential candidate for this purpose. We found that the protein target of levetiracetam, SV2A, is highly expressed by both NEPC cells and MCs infiltrating prostate adenocarcinoma, while it is low or negligible in adenocarcinoma cells. In vitro, levetiracetam inhibited the proliferation of NEPC cells and the degranulation of MCs. In mice bearing subcutaneous tumors levetiracetam was partially active on both NEPC and adenocarcinoma, the latter effect due to the inhibition of MMP9 release by MCs. Notably, in TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice subjected to surgical castration to mimic androgen deprivation therapy, levetiracetam reduced onset and frequency of both high grade prostatic intraepithelial neoplasia, adenocarcinoma and NEPC, thus increasing the number of cured mice showing only signs of tumor regression. Our results demonstrate that levetiracetam can directly restrain NEPC development after androgen deprivation, and that it can also block adenocarcinoma progression through the inhibition of some MCs functions. These findings open the possibility of further testing levetiracetam for the therapy of prostate cancer or of MC-mediated diseases.https://www.frontiersin.org/articles/10.3389/fimmu.2021.622001/fullprostate cancerneuroendocrine differentiationmast cellsdrug repurposingtumor microenvironmentmouse models |
| spellingShingle | Roberta Sulsenti Barbara Frossi Lucia Bongiovanni Valeria Cancila Paola Ostano Irene Fischetti Claudia Enriquez Francesca Guana Giovanna Chiorino Claudio Tripodo Carlo E. Pucillo Mario P. Colombo Elena Jachetti Repurposing of the Antiepileptic Drug Levetiracetam to Restrain Neuroendocrine Prostate Cancer and Inhibit Mast Cell Support to Adenocarcinoma Frontiers in Immunology prostate cancer neuroendocrine differentiation mast cells drug repurposing tumor microenvironment mouse models |
| title | Repurposing of the Antiepileptic Drug Levetiracetam to Restrain Neuroendocrine Prostate Cancer and Inhibit Mast Cell Support to Adenocarcinoma |
| title_full | Repurposing of the Antiepileptic Drug Levetiracetam to Restrain Neuroendocrine Prostate Cancer and Inhibit Mast Cell Support to Adenocarcinoma |
| title_fullStr | Repurposing of the Antiepileptic Drug Levetiracetam to Restrain Neuroendocrine Prostate Cancer and Inhibit Mast Cell Support to Adenocarcinoma |
| title_full_unstemmed | Repurposing of the Antiepileptic Drug Levetiracetam to Restrain Neuroendocrine Prostate Cancer and Inhibit Mast Cell Support to Adenocarcinoma |
| title_short | Repurposing of the Antiepileptic Drug Levetiracetam to Restrain Neuroendocrine Prostate Cancer and Inhibit Mast Cell Support to Adenocarcinoma |
| title_sort | repurposing of the antiepileptic drug levetiracetam to restrain neuroendocrine prostate cancer and inhibit mast cell support to adenocarcinoma |
| topic | prostate cancer neuroendocrine differentiation mast cells drug repurposing tumor microenvironment mouse models |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.622001/full |
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