Targeting CXCR4 with cell-penetrating pepducins in lymphoma and lymphocytic leukemia

Blood. 2012 Feb 16;119(7):1717-25. doi: 10.1182/blood-2011-04-347518. Epub 2011 Dec 20.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemistry
  • Drug Delivery Systems
  • Female
  • Humans
  • Interleukin Receptor Common gamma Subunit / genetics
  • Leukemia, Lymphoid / drug therapy*
  • Leukemia, Lymphoid / metabolism
  • Leukemia, Lymphoid / pathology
  • Lipopeptides / administration & dosage
  • Lipopeptides / chemical synthesis
  • Lipopeptides / chemistry
  • Lipopeptides / therapeutic use*
  • Lymphoma / drug therapy*
  • Lymphoma / metabolism
  • Lymphoma / pathology
  • Mice
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Models, Molecular
  • Molecular Targeted Therapy
  • Receptors, CXCR4 / antagonists & inhibitors*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Il2rg protein, mouse
  • Interleukin Receptor Common gamma Subunit
  • Lipopeptides
  • Receptors, CXCR4