Integrase-derived peptides together with CD24-targeted lentiviral particles inhibit the growth of CD24 expressing cancer cells.


Journal

Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562

Informations de publication

Date de publication:
06 2021
Historique:
received: 13 07 2020
accepted: 06 04 2021
revised: 02 03 2021
pubmed: 8 5 2021
medline: 13 1 2022
entrez: 7 5 2021
Statut: ppublish

Résumé

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.

Identifiants

pubmed: 33958722
doi: 10.1038/s41388-021-01779-5
pii: 10.1038/s41388-021-01779-5
pmc: PMC8175240
doi:

Substances chimiques

Antibodies, Monoclonal 0
CD24 Antigen 0
CD24 protein, human 0
Peptide Fragments 0
Integrases EC 2.7.7.-

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

3815-3825

Références

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Auteurs

Shiran Shapira (S)

Health Promotion Center and Integrated Cancer Prevention Center, Sourasky Medical Center, Tel-Aviv, Israel.
Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel.

Eynat Finkelshtein (E)

Zion Medical B.V, De Bilt, Netherlands.

Dina Kazanov (D)

Health Promotion Center and Integrated Cancer Prevention Center, Sourasky Medical Center, Tel-Aviv, Israel.

Esmira Naftali (E)

Zion Medical B.V, De Bilt, Netherlands.

Irena Stepansky (I)

Oncology Division, Tel Aviv Medical Center, Tel-Aviv, Israel.

Abraham Loyter (A)

Department of Biological Chemistry, The Alexander Institute of Life Sciences, Hebrew University, Jerusalem, Israel.

Daniel Elbirt (D)

Clinical Immunology, Allergy and AIDS Center Kaplan Medical Center, Affiliated with Hadassah-Hebrew University Medical School Jerusalem, Rehovot, Israel.

Mori Hay-Levy (M)

Health Promotion Center and Integrated Cancer Prevention Center, Sourasky Medical Center, Tel-Aviv, Israel.

Eli Brazowski (E)

Pathology Institute, Tel Aviv Sourasky Medical Center, Tel-Aviv, Israel.

Faina Bedny (F)

Pathology Institute, Tel Aviv Sourasky Medical Center, Tel-Aviv, Israel.

Roy Dekel (R)

Health Promotion Center and Integrated Cancer Prevention Center, Sourasky Medical Center, Tel-Aviv, Israel.

Dov Hershkovitz (D)

Pathology Institute, Tel Aviv Sourasky Medical Center, Tel-Aviv, Israel.

Arye Blachar (A)

Department of Radiology, Tel Aviv Sourasky Medical Center, Tel-Aviv, Israel.

Ido Wolf (I)

Oncology Division, Tel Aviv Medical Center, Tel-Aviv, Israel.

Nadir Arber (N)

Health Promotion Center and Integrated Cancer Prevention Center, Sourasky Medical Center, Tel-Aviv, Israel. nadir@tlvmc.gov.il.
Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel. nadir@tlvmc.gov.il.

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Classifications MeSH