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CXCR4-Targeted Necrosis-Inducing Peptidomimetic for Treating Breast Cancer
[Image: see text] Triple-negative breast cancer is an aggressive subtype with a high recurrence rate, potential for metastasis, and a poor prognosis. The chemokine receptor, CXCR4, is a promising molecular target in breast cancer therapy. Here, we have developed a CXCR4-targeted antitumor peptidomim...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10339399/ https://www.ncbi.nlm.nih.gov/pubmed/37457445 http://dx.doi.org/10.1021/acsomega.3c02415 |
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author | Akonnor, Abraham Makise, Masaki Kuniyasu, Akihiko |
author_facet | Akonnor, Abraham Makise, Masaki Kuniyasu, Akihiko |
author_sort | Akonnor, Abraham |
collection | PubMed |
description | [Image: see text] Triple-negative breast cancer is an aggressive subtype with a high recurrence rate, potential for metastasis, and a poor prognosis. The chemokine receptor, CXCR4, is a promising molecular target in breast cancer therapy. Here, we have developed a CXCR4-targeted antitumor peptidomimetic (named CTCE-KLAK), which is a fusion of the CXCR4 receptor antagonist CTCE-9908 and the D-form of proapoptotic peptide (KLAKLAK)(2), for the treatment of breast cancer. First, we investigated the in vitro antitumor activity of CTCE-KLAK against various breast cancer cells and noncancerous mammary epithelial cells. CTCE-KLAK showed cell-selective cytotoxicity and induced rapid necrotic cell death in breast cancer cells but not in normal cells. In contrast, unconjugated peptides such as the carboxylate analogues of CTCE-9908 and (D)(KLAKLAK)(2) were not cytotoxic to these cells. The tumor selectivity of CTCE-KLAK for cytotoxic activity depends on its internalization into tumor cells. There was no cleavage of caspase-3, caspase-7, or PARP1 in CTCE-KLAK-treated cells. In addition, cell death by CTCE-KLAK was not prevented by z-VAD-fmk, a pan-caspase inhibitor that inhibits cisplatin-induced cell death. These data indicate that the CTCE-KLAK conjugate is a cell-selective inducer of necrosis. Furthermore, we evaluated the in vivo antitumor activity of CTCE-KLAK in the 4T1 mouse metastatic breast cancer model. Intravenous administration of CTCE-KLAK significantly inhibited tumor growth and lung metastasis. Together, these findings suggest that the necrosis-inducing peptidomimetic CTCE-KLAK is a promising CXCR4-targeted agent for treating triple-negative breast cancer. |
format | Online Article Text |
id | pubmed-10339399 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-103393992023-07-14 CXCR4-Targeted Necrosis-Inducing Peptidomimetic for Treating Breast Cancer Akonnor, Abraham Makise, Masaki Kuniyasu, Akihiko ACS Omega [Image: see text] Triple-negative breast cancer is an aggressive subtype with a high recurrence rate, potential for metastasis, and a poor prognosis. The chemokine receptor, CXCR4, is a promising molecular target in breast cancer therapy. Here, we have developed a CXCR4-targeted antitumor peptidomimetic (named CTCE-KLAK), which is a fusion of the CXCR4 receptor antagonist CTCE-9908 and the D-form of proapoptotic peptide (KLAKLAK)(2), for the treatment of breast cancer. First, we investigated the in vitro antitumor activity of CTCE-KLAK against various breast cancer cells and noncancerous mammary epithelial cells. CTCE-KLAK showed cell-selective cytotoxicity and induced rapid necrotic cell death in breast cancer cells but not in normal cells. In contrast, unconjugated peptides such as the carboxylate analogues of CTCE-9908 and (D)(KLAKLAK)(2) were not cytotoxic to these cells. The tumor selectivity of CTCE-KLAK for cytotoxic activity depends on its internalization into tumor cells. There was no cleavage of caspase-3, caspase-7, or PARP1 in CTCE-KLAK-treated cells. In addition, cell death by CTCE-KLAK was not prevented by z-VAD-fmk, a pan-caspase inhibitor that inhibits cisplatin-induced cell death. These data indicate that the CTCE-KLAK conjugate is a cell-selective inducer of necrosis. Furthermore, we evaluated the in vivo antitumor activity of CTCE-KLAK in the 4T1 mouse metastatic breast cancer model. Intravenous administration of CTCE-KLAK significantly inhibited tumor growth and lung metastasis. Together, these findings suggest that the necrosis-inducing peptidomimetic CTCE-KLAK is a promising CXCR4-targeted agent for treating triple-negative breast cancer. American Chemical Society 2023-06-26 /pmc/articles/PMC10339399/ /pubmed/37457445 http://dx.doi.org/10.1021/acsomega.3c02415 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Akonnor, Abraham Makise, Masaki Kuniyasu, Akihiko CXCR4-Targeted Necrosis-Inducing Peptidomimetic for Treating Breast Cancer |
title | CXCR4-Targeted
Necrosis-Inducing Peptidomimetic for
Treating Breast Cancer |
title_full | CXCR4-Targeted
Necrosis-Inducing Peptidomimetic for
Treating Breast Cancer |
title_fullStr | CXCR4-Targeted
Necrosis-Inducing Peptidomimetic for
Treating Breast Cancer |
title_full_unstemmed | CXCR4-Targeted
Necrosis-Inducing Peptidomimetic for
Treating Breast Cancer |
title_short | CXCR4-Targeted
Necrosis-Inducing Peptidomimetic for
Treating Breast Cancer |
title_sort | cxcr4-targeted
necrosis-inducing peptidomimetic for
treating breast cancer |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10339399/ https://www.ncbi.nlm.nih.gov/pubmed/37457445 http://dx.doi.org/10.1021/acsomega.3c02415 |
work_keys_str_mv | AT akonnorabraham cxcr4targetednecrosisinducingpeptidomimeticfortreatingbreastcancer AT makisemasaki cxcr4targetednecrosisinducingpeptidomimeticfortreatingbreastcancer AT kuniyasuakihiko cxcr4targetednecrosisinducingpeptidomimeticfortreatingbreastcancer |