Targeting neuropilin-1 in human leukemia and lymphoma.
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 (F(F)/(Y)XLRS), 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.
David H. Koch Center, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
Katja
K
Karjalainen
Diana E
DE
Jaalouk
Carlos E
CE
Bueso-Ramos
Amado J
AJ
Zurita
Akihiko
A
Kuniyasu
Bedrich L
BL
Eckhardt
Frank C
FC
Marini
Benjamin
B
Lichtiger
Susan
S
O'Brien
Hagop M
HM
Kantarjian
Jorge E
JE
Cortes
Erkki
E
Koivunen
Wadih
W
Arap
Renata
R
Pasqualini
D000208:Acute Disease; D000595:Amino Acid Sequence; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites / Q000235:genetics; D001854:Bone Marrow Cells / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007150:Immunohistochemistry; D020014:K562 Cells; D007938:Leukemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008969:Molecular Sequence Data; D039942:Neuropilin-1 / Q000235:genetics / Q000378:metabolism*; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D019151:Peptide Library; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D034622:RNA Interference; D020298:U937 Cells
D009842:Oligopeptides; D019151:Peptide Library; D039942:Neuropilin-1