Targeting neuropilin-1 in human leukemia and lymphoma Academic Article uri icon

abstract

  • 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.

authors

  • Karjalainen, Katja
  • Jaalouk, Diana E
  • Bueso-Ramos, Carlos E
  • Zurita, Amado J
  • Kuniyasu, Akihiko
  • Eckhardt, Bedrich L
  • Marini, Frank C
  • Lichtiger, Benjamin
  • O'Brien, Susan
  • Kantarjian, Hagop M
  • Cortes, Jorge E
  • Koivunen, Erkki
  • Arap, Wadih
  • Pasqualini, Renata

publication date

  • January 20, 2011

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