APR-246 alone and in combination with a phosphatidylserine-targeting antibody inhibits lung metastasis of human triple-negative breast cancer cells in nude mice
Received 14 March 2019
Accepted for publication 18 July 2019
Published 31 July 2019 Volume 2019:11 Pages 249—259
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Melinda Thomas
Peer reviewer comments 4
Editor who approved publication: Professor Pranela Rameshwar
Yayun Liang,1 Cynthia Besch-Williford,2 Matthew T Cook,3 Anthony Belenchia,4 Rolf A Brekken,5 Salman M Hyder1
1Department 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, USA
Background: 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
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