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N-Terminal Modification of the Tetrapeptide Arg-Leu-Tyr-Glu, a Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) Antagonist, Improves Antitumor Activity by Increasing its Stability against Serum Peptidases

Jung-A Yun, Joohwan Kim, Yi-Yong Baek, Wonjin Park, Minsik Park, Suji Kim, Taesam Kim, Seunghwan Choi, Dooil Jeoung, Hansoo Lee, Moo-Ho Won, Ji-Yoon Kim, Kwon-Soo Ha, Young-Guen Kwon and Young-Myeong Kim
Molecular Pharmacology December 2019, 96 (6) 692-701; DOI: https://doi.org/10.1124/mol.119.117234
Jung-A Yun
Departments of Molecular and Cellular Biochemistry (J.-A.Y., J.K., Y.-Y.B., W.P., M.P., S.K., T.K., S.C., K.-S.H., Y.-M.K.) and Neurobiology, School of Medicine (M.-H.W.), Departments of Biochemistry, College of Natural Sciences (D.J.) and Life Sciences, College of Natural Sciences (H.L.), and Kangwon Institute of Inclusive Technology (J.K., Y.-M.K.), Kangwon National University, Chuncheon, Gangwon-do, and Department of Anesthesiology and Pain Medicine, Hanyang University Hospital, Seoul (J.-Y.K.), and Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul (Y.-G.K.), Korea
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Joohwan Kim
Departments of Molecular and Cellular Biochemistry (J.-A.Y., J.K., Y.-Y.B., W.P., M.P., S.K., T.K., S.C., K.-S.H., Y.-M.K.) and Neurobiology, School of Medicine (M.-H.W.), Departments of Biochemistry, College of Natural Sciences (D.J.) and Life Sciences, College of Natural Sciences (H.L.), and Kangwon Institute of Inclusive Technology (J.K., Y.-M.K.), Kangwon National University, Chuncheon, Gangwon-do, and Department of Anesthesiology and Pain Medicine, Hanyang University Hospital, Seoul (J.-Y.K.), and Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul (Y.-G.K.), Korea
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Yi-Yong Baek
Departments of Molecular and Cellular Biochemistry (J.-A.Y., J.K., Y.-Y.B., W.P., M.P., S.K., T.K., S.C., K.-S.H., Y.-M.K.) and Neurobiology, School of Medicine (M.-H.W.), Departments of Biochemistry, College of Natural Sciences (D.J.) and Life Sciences, College of Natural Sciences (H.L.), and Kangwon Institute of Inclusive Technology (J.K., Y.-M.K.), Kangwon National University, Chuncheon, Gangwon-do, and Department of Anesthesiology and Pain Medicine, Hanyang University Hospital, Seoul (J.-Y.K.), and Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul (Y.-G.K.), Korea
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Wonjin Park
Departments of Molecular and Cellular Biochemistry (J.-A.Y., J.K., Y.-Y.B., W.P., M.P., S.K., T.K., S.C., K.-S.H., Y.-M.K.) and Neurobiology, School of Medicine (M.-H.W.), Departments of Biochemistry, College of Natural Sciences (D.J.) and Life Sciences, College of Natural Sciences (H.L.), and Kangwon Institute of Inclusive Technology (J.K., Y.-M.K.), Kangwon National University, Chuncheon, Gangwon-do, and Department of Anesthesiology and Pain Medicine, Hanyang University Hospital, Seoul (J.-Y.K.), and Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul (Y.-G.K.), Korea
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Minsik Park
Departments of Molecular and Cellular Biochemistry (J.-A.Y., J.K., Y.-Y.B., W.P., M.P., S.K., T.K., S.C., K.-S.H., Y.-M.K.) and Neurobiology, School of Medicine (M.-H.W.), Departments of Biochemistry, College of Natural Sciences (D.J.) and Life Sciences, College of Natural Sciences (H.L.), and Kangwon Institute of Inclusive Technology (J.K., Y.-M.K.), Kangwon National University, Chuncheon, Gangwon-do, and Department of Anesthesiology and Pain Medicine, Hanyang University Hospital, Seoul (J.-Y.K.), and Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul (Y.-G.K.), Korea
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Suji Kim
Departments of Molecular and Cellular Biochemistry (J.-A.Y., J.K., Y.-Y.B., W.P., M.P., S.K., T.K., S.C., K.-S.H., Y.-M.K.) and Neurobiology, School of Medicine (M.-H.W.), Departments of Biochemistry, College of Natural Sciences (D.J.) and Life Sciences, College of Natural Sciences (H.L.), and Kangwon Institute of Inclusive Technology (J.K., Y.-M.K.), Kangwon National University, Chuncheon, Gangwon-do, and Department of Anesthesiology and Pain Medicine, Hanyang University Hospital, Seoul (J.-Y.K.), and Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul (Y.-G.K.), Korea
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Taesam Kim
Departments of Molecular and Cellular Biochemistry (J.-A.Y., J.K., Y.-Y.B., W.P., M.P., S.K., T.K., S.C., K.-S.H., Y.-M.K.) and Neurobiology, School of Medicine (M.-H.W.), Departments of Biochemistry, College of Natural Sciences (D.J.) and Life Sciences, College of Natural Sciences (H.L.), and Kangwon Institute of Inclusive Technology (J.K., Y.-M.K.), Kangwon National University, Chuncheon, Gangwon-do, and Department of Anesthesiology and Pain Medicine, Hanyang University Hospital, Seoul (J.-Y.K.), and Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul (Y.-G.K.), Korea
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Seunghwan Choi
Departments of Molecular and Cellular Biochemistry (J.-A.Y., J.K., Y.-Y.B., W.P., M.P., S.K., T.K., S.C., K.-S.H., Y.-M.K.) and Neurobiology, School of Medicine (M.-H.W.), Departments of Biochemistry, College of Natural Sciences (D.J.) and Life Sciences, College of Natural Sciences (H.L.), and Kangwon Institute of Inclusive Technology (J.K., Y.-M.K.), Kangwon National University, Chuncheon, Gangwon-do, and Department of Anesthesiology and Pain Medicine, Hanyang University Hospital, Seoul (J.-Y.K.), and Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul (Y.-G.K.), Korea
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Dooil Jeoung
Departments of Molecular and Cellular Biochemistry (J.-A.Y., J.K., Y.-Y.B., W.P., M.P., S.K., T.K., S.C., K.-S.H., Y.-M.K.) and Neurobiology, School of Medicine (M.-H.W.), Departments of Biochemistry, College of Natural Sciences (D.J.) and Life Sciences, College of Natural Sciences (H.L.), and Kangwon Institute of Inclusive Technology (J.K., Y.-M.K.), Kangwon National University, Chuncheon, Gangwon-do, and Department of Anesthesiology and Pain Medicine, Hanyang University Hospital, Seoul (J.-Y.K.), and Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul (Y.-G.K.), Korea
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Hansoo Lee
Departments of Molecular and Cellular Biochemistry (J.-A.Y., J.K., Y.-Y.B., W.P., M.P., S.K., T.K., S.C., K.-S.H., Y.-M.K.) and Neurobiology, School of Medicine (M.-H.W.), Departments of Biochemistry, College of Natural Sciences (D.J.) and Life Sciences, College of Natural Sciences (H.L.), and Kangwon Institute of Inclusive Technology (J.K., Y.-M.K.), Kangwon National University, Chuncheon, Gangwon-do, and Department of Anesthesiology and Pain Medicine, Hanyang University Hospital, Seoul (J.-Y.K.), and Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul (Y.-G.K.), Korea
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Moo-Ho Won
Departments of Molecular and Cellular Biochemistry (J.-A.Y., J.K., Y.-Y.B., W.P., M.P., S.K., T.K., S.C., K.-S.H., Y.-M.K.) and Neurobiology, School of Medicine (M.-H.W.), Departments of Biochemistry, College of Natural Sciences (D.J.) and Life Sciences, College of Natural Sciences (H.L.), and Kangwon Institute of Inclusive Technology (J.K., Y.-M.K.), Kangwon National University, Chuncheon, Gangwon-do, and Department of Anesthesiology and Pain Medicine, Hanyang University Hospital, Seoul (J.-Y.K.), and Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul (Y.-G.K.), Korea
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Ji-Yoon Kim
Departments of Molecular and Cellular Biochemistry (J.-A.Y., J.K., Y.-Y.B., W.P., M.P., S.K., T.K., S.C., K.-S.H., Y.-M.K.) and Neurobiology, School of Medicine (M.-H.W.), Departments of Biochemistry, College of Natural Sciences (D.J.) and Life Sciences, College of Natural Sciences (H.L.), and Kangwon Institute of Inclusive Technology (J.K., Y.-M.K.), Kangwon National University, Chuncheon, Gangwon-do, and Department of Anesthesiology and Pain Medicine, Hanyang University Hospital, Seoul (J.-Y.K.), and Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul (Y.-G.K.), Korea
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Kwon-Soo Ha
Departments of Molecular and Cellular Biochemistry (J.-A.Y., J.K., Y.-Y.B., W.P., M.P., S.K., T.K., S.C., K.-S.H., Y.-M.K.) and Neurobiology, School of Medicine (M.-H.W.), Departments of Biochemistry, College of Natural Sciences (D.J.) and Life Sciences, College of Natural Sciences (H.L.), and Kangwon Institute of Inclusive Technology (J.K., Y.-M.K.), Kangwon National University, Chuncheon, Gangwon-do, and Department of Anesthesiology and Pain Medicine, Hanyang University Hospital, Seoul (J.-Y.K.), and Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul (Y.-G.K.), Korea
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Young-Guen Kwon
Departments of Molecular and Cellular Biochemistry (J.-A.Y., J.K., Y.-Y.B., W.P., M.P., S.K., T.K., S.C., K.-S.H., Y.-M.K.) and Neurobiology, School of Medicine (M.-H.W.), Departments of Biochemistry, College of Natural Sciences (D.J.) and Life Sciences, College of Natural Sciences (H.L.), and Kangwon Institute of Inclusive Technology (J.K., Y.-M.K.), Kangwon National University, Chuncheon, Gangwon-do, and Department of Anesthesiology and Pain Medicine, Hanyang University Hospital, Seoul (J.-Y.K.), and Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul (Y.-G.K.), Korea
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Young-Myeong Kim
Departments of Molecular and Cellular Biochemistry (J.-A.Y., J.K., Y.-Y.B., W.P., M.P., S.K., T.K., S.C., K.-S.H., Y.-M.K.) and Neurobiology, School of Medicine (M.-H.W.), Departments of Biochemistry, College of Natural Sciences (D.J.) and Life Sciences, College of Natural Sciences (H.L.), and Kangwon Institute of Inclusive Technology (J.K., Y.-M.K.), Kangwon National University, Chuncheon, Gangwon-do, and Department of Anesthesiology and Pain Medicine, Hanyang University Hospital, Seoul (J.-Y.K.), and Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul (Y.-G.K.), Korea
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Abstract

The tetrapeptide Arg-Leu-Tyr-Glu (RLYE), a vascular endothelial growth factor (VEGF) receptor-2 antagonist, has been used previously either alone or in combination with chemotherapeutic drugs for treating colorectal cancer in a mouse model. We analyzed the half-life of the peptide and found that because of degradation by aminopeptidases B and N, it had a short half-life of 1.2 hours in the serum. Therefore, to increase the stability and potency of the peptide, we designed the modified peptide, N-terminally acetylated RLYE (Ac-RLYE), which had a strongly stabilized half-life of 8.8 hours in serum compared with the original parent peptide. The IC50 value of Ac-RLYE for VEGF-A-induced endothelial cell migration decreased to approximately 37.1 pM from 89.1 pM for the parent peptide. Using a mouse xenograft tumor model, we demonstrated that Ac-RLYE was more potent than RLYE in inhibiting tumor angiogenesis and growth, improving vascular integrity and normalization through enhanced endothelial cell junctions and pericyte coverage of the tumor vasculature, and impeding the infiltration of macrophages into tumor and their polarization to the M2 phenotype. Furthermore, combined treatment of Ac-RLYE and irinotecan exhibited synergistic effects on M1-like macrophage activation and apoptosis and growth inhibition of tumor cells. These findings provide evidence that the N-terminal acetylation augments the therapeutic effect of RLYE in solid tumors via inhibition of tumor angiogenesis, improvement of tumor vessel integrity and normalization, and enhancement of the livery and efficacy of the coadministered chemotherapeutic drugs.

SIGNIFICANCE STATEMENT The results of this study demonstrate that the N-terminal acetylation of the tetrapeptide RLYE (Ac-RLYE), a novel vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitor, significantly improves its serum stability, antiangiogenic activity, and vascular normalizing potency, resulting in enhanced therapeutic effect on solid tumors. Furthermore, the combined treatment of Ac-RLYE with the chemotherapeutic drug, irinotecan, synergistically enhanced its antitumor efficacy by improving the perfusion and delivery of the drug into the tumors and stimulating the conversion of the tumor-associated macrophages to an immunostimulatory M1-like antitumor phenotype.

Footnotes

    • Received May 13, 2019.
    • Accepted October 3, 2019.
  • ↵1 J.-A.Y., J.K., and Y.-Y.B. contributed equally to this work.

  • This work was supported by the National Research Foundation of Korea (NRF) and funded by the Korea Government (MSIP) (Grant NRF-2017R1A2B3004565).

  • https://doi.org/10.1124/mol.119.117234.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2019 by The Author(s)

This is an open access article distributed under the CC BY-NC Attribution 4.0 International license.

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Molecular Pharmacology: 96 (6)
Molecular Pharmacology
Vol. 96, Issue 6
1 Dec 2019
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N-Terminal Modification of the Tetrapeptide Arg-Leu-Tyr-Glu, a Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) Antagonist, Improves Antitumor Activity by Increasing its Stability against Serum Peptidases
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Research ArticleArticle

Serum Stabilization of the VEGFR-2 Antagonist RLYE

Jung-A Yun, Joohwan Kim, Yi-Yong Baek, Wonjin Park, Minsik Park, Suji Kim, Taesam Kim, Seunghwan Choi, Dooil Jeoung, Hansoo Lee, Moo-Ho Won, Ji-Yoon Kim, Kwon-Soo Ha, Young-Guen Kwon and Young-Myeong Kim
Molecular Pharmacology December 1, 2019, 96 (6) 692-701; DOI: https://doi.org/10.1124/mol.119.117234

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Research ArticleArticle

Serum Stabilization of the VEGFR-2 Antagonist RLYE

Jung-A Yun, Joohwan Kim, Yi-Yong Baek, Wonjin Park, Minsik Park, Suji Kim, Taesam Kim, Seunghwan Choi, Dooil Jeoung, Hansoo Lee, Moo-Ho Won, Ji-Yoon Kim, Kwon-Soo Ha, Young-Guen Kwon and Young-Myeong Kim
Molecular Pharmacology December 1, 2019, 96 (6) 692-701; DOI: https://doi.org/10.1124/mol.119.117234
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