title: The Spiegelmer NOX-A12, a novel CXCL12 inhibitor, interferes with chronic lymphocytic leukemia cell motility and causes chemosensitization.
abstract: The CXC chemokine ligand (CXCL12, or stromal cell-derived factor-1 as previously known) plays a critical role for homing and retention of chronic lymphocytic leukemia (CLL) cells in tissues such as the bone marrow (BM). In tissues, stromal cells constitutively secrete and present CXCL12 via cell-surface-bound glycosaminoglycans (GAGs), thereby attracting CLL cells and protecting them from cytotoxic drugs, a mechanism that may account for residual disease after conventional CLL therapy. NOX-A12, an RNA oligonucleotide in L-configuration (Spiegelmer) that binds and neutralizes CXCL12, was developed for interference with CXCL12 in the tumor microenvironment and for cell mobilization. Here, we examined effects of NOX-A12 on CLL cell migration and drug sensitivity. We found that NOX-A12 effectively inhibited CXCL12-induced chemotaxis of CLL cells. In contrast, NOX-A12 increased CLL migration underneath a confluent layer of BM stromal cells (BMSCs) due to interference with the CXCL12 gradient established by BMSCs. In particular, NOX-A12 competes with GAGs such as heparin for CXCL12 binding, leading to the release of CXCL12 from stromal cell-surface-bound GAGs, and thereby to neutralization of the chemokine. Furthermore, NOX-A12 sensitizes CLL cells toward bendamustine and fludarabine in BMSC cocultures. These data demonstrate that NOX-A12 effectively interferes with CLL cell migration and BMSC-mediated drug resistance, and establishes a rationale for clinical development of NOX-A12 in combination with conventional agents in CLL.
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX; and.
authors.forename: Julia
authors.initials: J
authors.lastname: Hoellenriegel
authors.forename: Dirk
authors.initials: D
authors.lastname: Zboralski
authors.forename: Christian
authors.initials: C
authors.lastname: Maasch
authors.forename: Nathalie Y
authors.initials: NY
authors.lastname: Rosin
authors.forename: William G
authors.initials: WG
authors.lastname: Wierda
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keating
authors.forename: Anna
authors.initials: A
authors.lastname: Kruschinski
authors.forename: Jan A
authors.initials: JA
authors.lastname: Burger
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D052157:Aptamers, Nucleotide / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D006801:Humans; D019169:Jurkat Cells; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology*; D008214:Lymphocytes / Q000187:drug effects / Q000502:physiology; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D057688:Transcellular Cell Migration / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D052157:Aptamers, Nucleotide; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; C587878:NOX-A12; D011994:Recombinant Proteins