Oncotarget

Research Papers:

Toward the development of a novel non-RGD cyclic peptide drug conjugate for treatment of human metastatic melanoma

Boris Redko, Helena Tuchinsky, Tamar Segal, Dror Tobi, Galia Luboshits, Osnat Ashur-Fabian, Albert Pinhasov, Gabi Gerlitz _ and Gary Gellerman

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Oncotarget. 2017; 8:757-768. https://doi.org/10.18632/oncotarget.12748

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Abstract

Boris Redko1, Helena Tuchinsky2, Tamar Segal2, Dror Tobi2,3, Galia Luboshits4, Osnat Ashur-Fabian5, Albert Pinhasov2, Gabi Gerlitz2, Gary Gellerman1

1Department of Chemical Sciences, Ariel University, Ariel, Israel

2Department of Molecular Biology, Ariel University, Ariel, Israel

3Department of Computer Science, Ariel University, Ariel, Israel

4Department of Chemical Engineering, Ariel University, Ariel, Israel

5Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

Correspondence to:

Gabi Gerlitz, email: [email protected]

Gary Gellerman, email: [email protected]

Keywords: targeted drug delivery, human metastatic melanoma, Integrin αvβ3, non-RGD, conjugate

Received: July 22, 2016     Accepted: October 10, 2016     Published: October 19, 2016

GRAPHICAL ABSTRACT

ABSTRACT

The newly discovered short (9 amino acid) non-RGD S-S bridged cyclic peptide ALOS-4 (H-cycl(Cys-Ser-Ser-Ala-Gly-Ser-Leu-Phe-Cys)-OH), which binds to integrin αvβ3 is investigated as peptide carrier for targeted drug delivery against human metastatic melanoma. ALOS4 binds specifically the αvβ3 overexpressing human metastatic melanoma WM-266-4 cell line both in vitro and in ex vivo assays. Coupling ALOS4 to the topoisomerase I inhibitor Camptothecin (ALOS4-CPT) increases the cytotoxicity of CPT against human metastatic melanoma cells while reduces dramatically the cytotoxicity against non-cancerous cells as measured by the levels of γH2A.X, active caspase 3 and cell viability. Moreover, conjugating ALOS4 to CPT even increases the chemo-stability of CPT under physiological pH. Bioinformatic analysis using Rosetta platform revealed potential docking sites of ALOS4 on the αvβ3 integrin which are distinct from the RGD binding sites. We propose to use this specific non-RGD cyclic peptide as the therapeutic carrier for conjugation of drugs in order to improve efficacy and reduce toxicity of currently available treatments of human malignant melanoma.


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