title: CXCR4 inhibitor AMD3100 disrupts the interaction of multiple myeloma cells with the bone marrow microenvironment and enhances their sensitivity to therapy.
abstract: The interaction of multiple myeloma (MM) cells with their microenvironment in the bone marrow (BM) provides a protective environment and resistance to therapeutic agents. We hypothesized that disruption of the interaction of MM cells with their BM milieu would lead to their sensitization to therapeutic agents such as bortezomib, melphalan, doxorubicin, and dexamethasone. We report that the CXCR4 inhibitor AMD3100 induces disruption of the interaction of MM cells with the BM reflected by mobilization of MM cells into the circulation in vivo, with kinetics that differed from that of hematopoietic stem cells. AMD3100 enhanced sensitivity of MM cell to multiple therapeutic agents in vitro by disrupting adhesion of MM cells to bone marrow stromal cells (BMSCs). Moreover, AMD3100 increased mobilization of MM cells to the circulation in vivo, increased the ratio of apoptotic circulating MM cells, and enhanced the tumor reduction induced by bortezomib. Mechanistically, AMD3100 significantly inhibited Akt phosphorylation and enhanced poly(ADP-ribose) polymerase (PARP) cleavage as a result of bortezomib, in the presence of BMSCs in coculture. These experiments provide a proof of concept for the use of agents that disrupt interaction with the microenvironment for enhancement of efficacy of cytotoxic agents in cancer therapy.
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Abdel Kareem
authors.initials: AK
authors.lastname: Azab
authors.forename: Judith M
authors.initials: JM
authors.lastname: Runnels
authors.forename: Costas
authors.initials: C
authors.lastname: Pitsillides
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Moreau
authors.forename: Feda
authors.initials: F
authors.lastname: Azab
authors.forename: Xavier
authors.initials: X
authors.lastname: Leleu
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Jia
authors.forename: Renee
authors.initials: R
authors.lastname: Wright
authors.forename: Beatriz
authors.initials: B
authors.lastname: Ospina
authors.forename: Alicia L
authors.initials: AL
authors.lastname: Carlson
authors.forename: Clemens
authors.initials: C
authors.lastname: Alt
authors.forename: Nicholas
authors.initials: N
authors.lastname: Burwick
authors.forename: Aldo M
authors.initials: AM
authors.lastname: Roccaro
authors.forename: Hai T
authors.initials: HT
authors.lastname: Ngo
authors.forename: Mena
authors.initials: M
authors.lastname: Farag
authors.forename: Molly R
authors.initials: MR
authors.lastname: Melhem
authors.forename: Antonio
authors.initials: A
authors.lastname: Sacco
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.forename: Barrett J
authors.initials: BJ
authors.lastname: Rollins
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: Charles P
authors.initials: CP
authors.lastname: Lin
authors.forename: Irene M
authors.initials: IM
authors.lastname: Ghobrial
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001596:Benzylamines; D001853:Bone Marrow / Q000378:metabolism*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D003114:Colony-Forming Units Assay; D000080027:Cyclams; D019008:Drug Resistance, Neoplasm; D005353:Fibronectins / Q000378:metabolism; D005434:Flow Cytometry; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D039041:Integrin alpha4beta1 / Q000235:genetics / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D017154:Stromal Cells / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D019380:Anti-HIV Agents; D000970:Antineoplastic Agents; D001596:Benzylamines; D001897:Boronic Acids; C527276:CXCR4 protein, human; D000080027:Cyclams; D005353:Fibronectins; D006571:Heterocyclic Compounds; D039041:Integrin alpha4beta1; D011719:Pyrazines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D018799:Intercellular Adhesion Molecule-1; D000069286:Bortezomib; C088327:plerixafor