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Integrase-derived peptides together with CD24-targeted lentiviral particles inhibit the growth of CD24 expressing cancer cells
The integration of viral DNA into the host genome is mediated by viral integrase, resulting in the accumulation of double-strand breaks. Integrase-derived peptides (INS and INR) increase the number of integration events, leading to escalated genomic instability that induces apoptosis. CD24 is a surf...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175240/ https://www.ncbi.nlm.nih.gov/pubmed/33958722 http://dx.doi.org/10.1038/s41388-021-01779-5 |
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author | Shapira, Shiran Finkelshtein, Eynat Kazanov, Dina Naftali, Esmira Stepansky, Irena Loyter, Abraham Elbirt, Daniel Hay-Levy, Mori Brazowski, Eli Bedny, Faina Dekel, Roy Hershkovitz, Dov Blachar, Arye Wolf, Ido Arber, Nadir |
author_facet | Shapira, Shiran Finkelshtein, Eynat Kazanov, Dina Naftali, Esmira Stepansky, Irena Loyter, Abraham Elbirt, Daniel Hay-Levy, Mori Brazowski, Eli Bedny, Faina Dekel, Roy Hershkovitz, Dov Blachar, Arye Wolf, Ido Arber, Nadir |
author_sort | Shapira, Shiran |
collection | PubMed |
description | The integration of viral DNA into the host genome is mediated by viral integrase, resulting in the accumulation of double-strand breaks. Integrase-derived peptides (INS and INR) increase the number of integration events, leading to escalated genomic instability that induces apoptosis. CD24 is a surface protein expressed mostly in cancer cells and is very rarely found in normal cells. Here, we propose a novel targeted cancer therapeutic platform based on the lentiviral integrase, stimulated by integrase-derived peptides, that are specifically delivered to cancerous cells via CD24 antigen-antibody targeting. INS and INR were synthesized and humanized and anti-CD24 antibodies were fused to the lentivirus envelope. The activity, permeability, stability, solubility, and toxicity of these components were analyzed. Cell death was measured by fluorescent microscopy and enzymatic assays and potency were tested in vitro and in vivo. Lentivirus particles, containing non-functional DNA led to massive cell death (40–70%). Raltegravir, an antiretroviral drug, inhibited the induction of apoptosis. In vivo, single and repeated administrations of INS/INR were well tolerated without any adverse effects. Tumor development in nude mice was significantly inhibited (by 50%) as compared to the vehicle arm. In summary, a novel and generic therapeutic platform for selective cancer cell eradication with excellent efficacy and safety are presented. |
format | Online Article Text |
id | pubmed-8175240 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-81752402021-06-17 Integrase-derived peptides together with CD24-targeted lentiviral particles inhibit the growth of CD24 expressing cancer cells Shapira, Shiran Finkelshtein, Eynat Kazanov, Dina Naftali, Esmira Stepansky, Irena Loyter, Abraham Elbirt, Daniel Hay-Levy, Mori Brazowski, Eli Bedny, Faina Dekel, Roy Hershkovitz, Dov Blachar, Arye Wolf, Ido Arber, Nadir Oncogene Article The integration of viral DNA into the host genome is mediated by viral integrase, resulting in the accumulation of double-strand breaks. Integrase-derived peptides (INS and INR) increase the number of integration events, leading to escalated genomic instability that induces apoptosis. CD24 is a surface protein expressed mostly in cancer cells and is very rarely found in normal cells. Here, we propose a novel targeted cancer therapeutic platform based on the lentiviral integrase, stimulated by integrase-derived peptides, that are specifically delivered to cancerous cells via CD24 antigen-antibody targeting. INS and INR were synthesized and humanized and anti-CD24 antibodies were fused to the lentivirus envelope. The activity, permeability, stability, solubility, and toxicity of these components were analyzed. Cell death was measured by fluorescent microscopy and enzymatic assays and potency were tested in vitro and in vivo. Lentivirus particles, containing non-functional DNA led to massive cell death (40–70%). Raltegravir, an antiretroviral drug, inhibited the induction of apoptosis. In vivo, single and repeated administrations of INS/INR were well tolerated without any adverse effects. Tumor development in nude mice was significantly inhibited (by 50%) as compared to the vehicle arm. In summary, a novel and generic therapeutic platform for selective cancer cell eradication with excellent efficacy and safety are presented. Nature Publishing Group UK 2021-05-06 2021 /pmc/articles/PMC8175240/ /pubmed/33958722 http://dx.doi.org/10.1038/s41388-021-01779-5 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Shapira, Shiran Finkelshtein, Eynat Kazanov, Dina Naftali, Esmira Stepansky, Irena Loyter, Abraham Elbirt, Daniel Hay-Levy, Mori Brazowski, Eli Bedny, Faina Dekel, Roy Hershkovitz, Dov Blachar, Arye Wolf, Ido Arber, Nadir Integrase-derived peptides together with CD24-targeted lentiviral particles inhibit the growth of CD24 expressing cancer cells |
title | Integrase-derived peptides together with CD24-targeted lentiviral particles inhibit the growth of CD24 expressing cancer cells |
title_full | Integrase-derived peptides together with CD24-targeted lentiviral particles inhibit the growth of CD24 expressing cancer cells |
title_fullStr | Integrase-derived peptides together with CD24-targeted lentiviral particles inhibit the growth of CD24 expressing cancer cells |
title_full_unstemmed | Integrase-derived peptides together with CD24-targeted lentiviral particles inhibit the growth of CD24 expressing cancer cells |
title_short | Integrase-derived peptides together with CD24-targeted lentiviral particles inhibit the growth of CD24 expressing cancer cells |
title_sort | integrase-derived peptides together with cd24-targeted lentiviral particles inhibit the growth of cd24 expressing cancer cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175240/ https://www.ncbi.nlm.nih.gov/pubmed/33958722 http://dx.doi.org/10.1038/s41388-021-01779-5 |
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