APR-246 alone and in combination with a phosphatidylserine-targeting antibody inhibits lung metastasis of human triple-negative breast cancer cells in nude mice

Yayun Liang,1 Cynthia Besch-Williford,2 Matthew T Cook,3 Anthony Belenchia,4 Rolf A Brekken,5 Salman M Hyder11Department of Biomedical Sciences and Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA; 2IDEXX BioAnalytics, Columbia, MO, USA; 3Department of Biology, Washbu...

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Autores principales:	Liang Y, Besch-Williford C, Cook MT, Belenchia A, Brekken RA, Hyder SM
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2019
Materias:	breast cancer metastasis blood-vessel targeting agent p53 APR-246 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/38810a00ce0746dcbc85259a8277aefe
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spelling	oai:doaj.org-article:38810a00ce0746dcbc85259a8277aefe2021-12-02T06:43:55ZAPR-246 alone and in combination with a phosphatidylserine-targeting antibody inhibits lung metastasis of human triple-negative breast cancer cells in nude mice1179-1314https://doaj.org/article/38810a00ce0746dcbc85259a8277aefe2019-07-01T00:00:00Zhttps://www.dovepress.com/apr-246-alone-and-in-combination-with-a-phosphatidylserine-targeting-a-peer-reviewed-article-BCTThttps://doaj.org/toc/1179-1314Yayun Liang,1 Cynthia Besch-Williford,2 Matthew T Cook,3 Anthony Belenchia,4 Rolf A Brekken,5 Salman M Hyder11Department of Biomedical Sciences and Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA; 2IDEXX BioAnalytics, Columbia, MO, USA; 3Department of Biology, Washburn University, Topeka, KS, USA; 4Department of Nutrition and Exercise Physiology and Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA; 5Hamon Center for Therapeutic Oncology Research and Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USABackground: Approximately 15–20% of all human breast cancers are classified as triple-negative because they lack estrogen and progesterone receptors and Her-2-neu, which are commonly targeted by chemotherapeutic drugs. New treatment strategies are therefore urgently needed to combat triple-negative breast cancers (TNBCs). Almost 80% of the triple-negative tumors express mutant p53 (mtp5), a functionally defective tumor suppressor protein. Whereas wild-type p53 (wtp53) promotes cell-cycle arrest and apoptosis and inhibits vascular endothelial growth factor-dependent angiogenesis, mtp53 fails to regulate these functions, resulting in tumor vascularization, growth, resistance to chemotherapy, and metastasis. Restoration of p53 function is therefore a promising drug-targeted strategy for suppressing TNBC metastasis.Methods: APR-246 is a small-molecule drug that reactivates mtp53, thereby restoring p53 function. In this study, we sought to determine whether administration of APR-246, either alone or in combination with 2aG4, an antibody that targets phosphatidylserine residues on tumor blood vessels and disrupts tumor vasculature, effectively inhibits stem cell-like characteristics of tumor cells and migration in vitro, and metastasis of human mtp53-expressing TNBC cells to the lungs in mouse models.Results: APR-246 reduced both the stem cell-like properties and migration of TNBC cells in vitro. In mouse models, administration of either APR-246 or 2aG4 reduced metastasis of TNBC cells to the lungs; a combination of the two diminished lung metastasis to the same extent as either agent alone. Combination treatment significantly reduced the incidence of lung metastasis compared either single agent alone.Conclusion: Metastasis of human mtp53-expressing TNBC cells to the lungs of nude mice is inhibited by the treatment that combines activation of mtp53 with targeting of phosphatidylserine residues on tumor blood vessels. We contend therefore that our findings strongly support the use of combination treatment involving mtp53 activation and immunotherapy in patients with TNBC.Keywords: breast cancer, metastasis, blood-vessel targeting agent, p53, APR-246Liang YBesch-Williford CCook MTBelenchia ABrekken RAHyder SMDove Medical Pressarticlebreast cancermetastasisblood-vessel targeting agentp53APR-246Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENBreast Cancer: Targets and Therapy, Vol Volume 11, Pp 249-259 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	breast cancer metastasis blood-vessel targeting agent p53 APR-246 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	breast cancer metastasis blood-vessel targeting agent p53 APR-246 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Liang Y Besch-Williford C Cook MT Belenchia A Brekken RA Hyder SM APR-246 alone and in combination with a phosphatidylserine-targeting antibody inhibits lung metastasis of human triple-negative breast cancer cells in nude mice
description	Yayun Liang,1 Cynthia Besch-Williford,2 Matthew T Cook,3 Anthony Belenchia,4 Rolf A Brekken,5 Salman M Hyder11Department of Biomedical Sciences and Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA; 2IDEXX BioAnalytics, Columbia, MO, USA; 3Department of Biology, Washburn University, Topeka, KS, USA; 4Department of Nutrition and Exercise Physiology and Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA; 5Hamon Center for Therapeutic Oncology Research and Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USABackground: Approximately 15–20% of all human breast cancers are classified as triple-negative because they lack estrogen and progesterone receptors and Her-2-neu, which are commonly targeted by chemotherapeutic drugs. New treatment strategies are therefore urgently needed to combat triple-negative breast cancers (TNBCs). Almost 80% of the triple-negative tumors express mutant p53 (mtp5), a functionally defective tumor suppressor protein. Whereas wild-type p53 (wtp53) promotes cell-cycle arrest and apoptosis and inhibits vascular endothelial growth factor-dependent angiogenesis, mtp53 fails to regulate these functions, resulting in tumor vascularization, growth, resistance to chemotherapy, and metastasis. Restoration of p53 function is therefore a promising drug-targeted strategy for suppressing TNBC metastasis.Methods: APR-246 is a small-molecule drug that reactivates mtp53, thereby restoring p53 function. In this study, we sought to determine whether administration of APR-246, either alone or in combination with 2aG4, an antibody that targets phosphatidylserine residues on tumor blood vessels and disrupts tumor vasculature, effectively inhibits stem cell-like characteristics of tumor cells and migration in vitro, and metastasis of human mtp53-expressing TNBC cells to the lungs in mouse models.Results: APR-246 reduced both the stem cell-like properties and migration of TNBC cells in vitro. In mouse models, administration of either APR-246 or 2aG4 reduced metastasis of TNBC cells to the lungs; a combination of the two diminished lung metastasis to the same extent as either agent alone. Combination treatment significantly reduced the incidence of lung metastasis compared either single agent alone.Conclusion: Metastasis of human mtp53-expressing TNBC cells to the lungs of nude mice is inhibited by the treatment that combines activation of mtp53 with targeting of phosphatidylserine residues on tumor blood vessels. We contend therefore that our findings strongly support the use of combination treatment involving mtp53 activation and immunotherapy in patients with TNBC.Keywords: breast cancer, metastasis, blood-vessel targeting agent, p53, APR-246
format	article
author	Liang Y Besch-Williford C Cook MT Belenchia A Brekken RA Hyder SM
author_facet	Liang Y Besch-Williford C Cook MT Belenchia A Brekken RA Hyder SM
author_sort	Liang Y
title	APR-246 alone and in combination with a phosphatidylserine-targeting antibody inhibits lung metastasis of human triple-negative breast cancer cells in nude mice
title_short	APR-246 alone and in combination with a phosphatidylserine-targeting antibody inhibits lung metastasis of human triple-negative breast cancer cells in nude mice
title_full	APR-246 alone and in combination with a phosphatidylserine-targeting antibody inhibits lung metastasis of human triple-negative breast cancer cells in nude mice
title_fullStr	APR-246 alone and in combination with a phosphatidylserine-targeting antibody inhibits lung metastasis of human triple-negative breast cancer cells in nude mice
title_full_unstemmed	APR-246 alone and in combination with a phosphatidylserine-targeting antibody inhibits lung metastasis of human triple-negative breast cancer cells in nude mice
title_sort	apr-246 alone and in combination with a phosphatidylserine-targeting antibody inhibits lung metastasis of human triple-negative breast cancer cells in nude mice
publisher	Dove Medical Press
publishDate	2019
url	https://doaj.org/article/38810a00ce0746dcbc85259a8277aefe
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APR-246 alone and in combination with a phosphatidylserine-targeting antibody inhibits lung metastasis of human triple-negative breast cancer cells in nude mice

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