TY - JOUR
T1 - 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
AU - Hamasaki, Makoto
AU - Hideshima, Teru
AU - Tassone, Pierfrancesco
AU - Neri, Paola
AU - Ishitsuka, Kenji
AU - Yasui, Hiroshi
AU - Shiraishi, Norihiko
AU - Raje, Noopur
AU - Kumar, Shaji
AU - Picker, Donald H.
AU - Jacob, Gary S.
AU - Richardson, Paul G.
AU - Munshi, Nikhil C.
AU - Anderson, Kenneth C.
PY - 2005/6/1
Y1 - 2005/6/1
N2 - 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 (phosphatidyl-inositol 3-kinase) target (Akt), but not extracellular signal-regulated kinase 1 and 2 (ERKV2), inhibits phosphorylation triggered by IL-6, and also inhibits inhibitorKBa (IκBα) and nuclear factor κB(NFκB) p65 phosphorylation triggered by tumor necrosis factor α (TNF-α). 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.
AB - 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 (phosphatidyl-inositol 3-kinase) target (Akt), but not extracellular signal-regulated kinase 1 and 2 (ERKV2), inhibits phosphorylation triggered by IL-6, and also inhibits inhibitorKBa (IκBα) and nuclear factor κB(NFκB) p65 phosphorylation triggered by tumor necrosis factor α (TNF-α). 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=21144440687&partnerID=8YFLogxK
U2 - 10.1182/blood-2004-09-3794
DO - 10.1182/blood-2004-09-3794
M3 - Article
C2 - 15705788
AN - SCOPUS:21144440687
SN - 0006-4971
VL - 105
SP - 4470
EP - 4476
JO - Blood
JF - Blood
IS - 11
ER -