title: Targeting CXCR4 with cell-penetrating pepducins in lymphoma and lymphocytic leukemia.
abstract: The chemokine receptor CXCR4, which normally regulates stromal stem cell interactions in the bone marrow, is highly expressed on a variety of malignant hematologic cells, including lymphoma and lymphocytic leukemias. A new treatment concept has arisen wherein CXCR4 may be an effective therapeutic target as an adjunct to treatment of hematologic neoplasms with chemo- and immunotherapy. In the present study, we developed pepducins, cell-penetrating lipopeptide antagonists of CXCR4, to interdict CXCL12-CXCR4 transmembrane signaling to intracellular G-proteins. We demonstrate that pepducins targeting the first (i1) or third (i3) intracellular loops of CXCR4 completely abrogate CXCL12-mediated cell migration of lymphocytic leukemias and lymphomas. Stromal-cell coculture protects lymphoma cells from apoptosis in response to treatment with the CD20-targeted Ab rituximab. However, combination treatment with CXCR4 pepducins and rituximab significantly increases the apoptotic effect of rituximab. Furthermore, treatment of mice bearing disseminated lymphoma xenografts with pepducins alone or in combination with rituximab significantly increased their survival. These data demonstrate that CXCL12-CXCR4 signaling can be effectively inhibited by cell-penetrating pepducins, which represents a potential new treatment strategy for lymphoid malignancies.
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
authors.forename: Katie
authors.initials: K
authors.lastname: O'Callaghan
authors.forename: Lydia
authors.initials: L
authors.lastname: Lee
authors.forename: Nga
authors.initials: N
authors.lastname: Nguyen
authors.forename: Mo-Ying
authors.initials: MY
authors.lastname: Hsieh
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Kaneider
authors.forename: Andreas K
authors.initials: AK
authors.lastname: Klein
authors.forename: Kellie
authors.initials: K
authors.lastname: Sprague
authors.forename: Richard A
authors.initials: RA
authors.lastname: Van Etten
authors.forename: Athan
authors.initials: A
authors.lastname: Kuliopulos
authors.forename: Lidija
authors.initials: L
authors.lastname: Covic
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics; D007945:Leukemia, Lymphoid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D055666:Lipopeptides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D008223:Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D055666:Lipopeptides; D019718:Receptors, CXCR4