1. Targeting neuropilin-1 in human leukemia and lymphoma
- Author
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Bedrich L. Eckhardt, Benjamin Lichtiger, Katja Karjalainen, Hagop M. Kantarjian, Jorge E. Cortes, Carlos E. Bueso-Ramos, Renata Pasqualini, Susan O'Brien, Akihiko Kuniyasu, Frank C. Marini, Erkki Koivunen, Wadih Arap, Amado J. Zurita, and Diana E. Jaalouk
- Subjects
Lymphoma ,Apoptosis ,Biochemistry ,0302 clinical medicine ,hemic and lymphatic diseases ,Neuropilin 1 ,0303 health sciences ,Leukemia ,Myeloid Neoplasia ,Hematology ,U937 Cells ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Immunohistochemistry ,3. Good health ,medicine.anatomical_structure ,Leukemia, Myeloid ,030220 oncology & carcinogenesis ,Acute Disease ,RNA Interference ,Oligopeptides ,Protein Binding ,medicine.medical_specialty ,Cell Survival ,Molecular Sequence Data ,Immunology ,Bone Marrow Cells ,Biology ,03 medical and health sciences ,Myelogenous ,Peptide Library ,Cell Line, Tumor ,Internal medicine ,medicine ,Humans ,Amino Acid Sequence ,Peptide library ,Cell Proliferation ,030304 developmental biology ,Binding Sites ,Dose-Response Relationship, Drug ,Cell Biology ,medicine.disease ,Virology ,Neuropilin-1 ,Targeted drug delivery ,Cancer research ,Bone marrow ,K562 Cells ,K562 cells - Abstract
Targeted drug delivery offers an opportunity for the development of safer and more effective therapies for the treatment of cancer. In this study, we sought to identify short, cell-internalizing peptide ligands that could serve as directive agents for specific drug delivery in hematologic malignancies. By screening of human leukemia cells with a combinatorial phage display peptide library, we isolated a peptide motif, sequence Phe-Phe/Tyr-Any-Leu-Arg-Ser (FF/YXLRS), which bound to different leukemia cell lines and to patient-derived bone marrow samples. The motif was internalized through a receptor-mediated pathway, and we next identified the corresponding receptor as the transmembrane glycoprotein neuropilin-1 (NRP-1). Moreover, we observed a potent anti-leukemia cell effect when the targeting motif was synthesized in tandem to the pro-apoptotic sequence D(KLAKLAK)2. Finally, our results confirmed increased expression of NRP-1 in representative human leukemia and lymphoma cell lines and in a panel of bone marrow specimens obtained from patients with acute lymphoblastic leukemia or acute myelogenous leukemia compared with normal bone marrow. These results indicate that NRP-1 could potentially be used as a target for ligand-directed therapy in human leukemias and lymphomas and that the prototype CGFYWLRSC-GG-D(KLAKLAK)2 is a promising drug candidate in this setting.
- Published
- 2011