title: Azaspirane (N-N-diethyl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine) inhibits human multiple myeloma cell growth in the bone marrow milieu in vitro and in vivo.
abstract: Azaspirane (N-N-diethyl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine; trade name, Atiprimod) is an orally bioavailable cationic amphiphilic compound that significantly inhibits production of interleukin 6 (IL-6) and inflammation in rat arthritis and autoimmune animal models. We here characterize the effect of atiprimod on human multiple myeloma (MM) cells. Azaspirane significantly inhibited growth and induced caspase-mediated apoptosis in drug-sensitive and drug-resistant MM cell lines, as well as patient MM cells. IL-6, insulin-like growth factor 1 (IGF-1), or adherence of MM cells to bone marrow stromal cells (BMSCs) did not protect against atiprimod-induced apoptosis. Both conventional (dexamethasone, doxorubicin, melphalan) and novel (arsenic trioxide) agents augment apoptosis induced by atiprimod. Azaspirane inhibits signal transducer activator of transcription 3 (STAT3) and a PI3-K (phosphatidylinositol 3-kinase) target (Akt), but not extracellular signal-regulated kinase 1 and 2 (ERK1/2), inhibits phosphorylation triggered by IL-6, and also inhibits inhibitorkappaBalpha (IkappaBalpha) and nuclear factor kappaB (NFkappaB) p65 phosphorylation triggered by tumor necrosis factor alpha (TNF-alpha). Of importance, azaspirane inhibits both IL-6 and vascular endothelial growth factor (VEGF) secretion in BMSCs triggered by MM cell binding and also inhibits angiogenesis on human umbilical vein cells (HUVECs). Finally, azaspirane demonstrates in vivo antitumor activity against human MM cell growth in severe combined immunodeficient (SCID) mice. These results, therefore, show that azaspirane both induces MM cell apoptosis and inhibits cytokine secretion in the BM milieu, providing the framework for clinical trials to improve patient outcome in MM.
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Mayer 557, 44 Binney St, Boston, MA 02115, USA.
authors.forename: Makoto
authors.initials: M
authors.lastname: Hamasaki
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Tassone
authors.forename: Paola
authors.initials: P
authors.lastname: Neri
authors.forename: Kenji
authors.initials: K
authors.lastname: Ishitsuka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yasui
authors.forename: Norihiko
authors.initials: N
authors.lastname: Shiraishi
authors.forename: Noopur
authors.initials: N
authors.lastname: Raje
authors.forename: Shaji
authors.initials: S
authors.lastname: Kumar
authors.forename: Donald H
authors.initials: DH
authors.lastname: Picker
authors.forename: Gary S
authors.initials: GS
authors.lastname: Jacob
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001853:Bone Marrow / Q000473:pathology*; D002450:Cell Communication; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013141:Spiro Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
chemical_list: D000970:Antineoplastic Agents; D015850:Interleukin-6; D013141:Spiro Compounds; D042461:Vascular Endothelial Growth Factor A; D000093242:Interleukin-6 Inhibitors; C099015:azaspirane