![]() In this report, we demonstrate that azaspirane induces potent cytotoxicity, at least in part, by inhibiting IL-6. 20 - 22 For example, it significantly inhibits inflammation and protects against joint erosion in animal models of arthritis. 16 - 19Īzaspirane ( N-N-diethyl-8,8-dipropyl-2-azaspiro decane-2-propanamine trade name, Atiprimod) is an orally bioavailable cationic amphiphilic compound, which has been extensively studied in a variety of animal models of autoimmune disease and transplantation. 13 - 15 Importantly, novel biologically based treatments that target not only the MM cell but also MM cell–host interactions and cytokines in the BM microenvironment can overcome drug resistance in both preclinical and early clinical studies. 6 - 10 Furthermore, the bone marrow (BM) microenvironment also confers drug resistance in MM cells via at least 2 different mechanisms: adhesion of MM cells to fibronectin confers cell adhesion–mediated drug resistance (CAM-DR), associated with induction of p27 Kip1 and G 1 growth arrest, 11, 12 and cytokines (ie, interleukin 6 and insulin-like growth factor 1 ) in the BM milieu induce Janus kinase 2 (JAK2)/signal transducers and activators of transcription 3 (STAT3), phosphatidylinositol 3-kinase (PI3-K)/a PI3-K target (Akt) signaling, or both, which mediates resistance to conventional therapies. 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.ĭespite treatment with alkylating agents, anthracyclines, and corticosteroids, 1, 2 as well as high-dose therapy and stem cell transplantation, 3 - 5 multiple myeloma (MM) remains incurable due to both intrinsic and acquired drug resistance. Finally, azaspirane demonstrates in vivo antitumor activity against human MM cell growth in severe combined immunodeficient (SCID) mice. 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). 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 inhibitorκBα (IκBα) and nuclear factor κB (NFκB) p65 phosphorylation triggered by tumor necrosis factor α (TNF-α). ![]() ![]() Both conventional (dexamethasone, doxorubicin, melphalan) and novel (arsenic trioxide) agents augment apoptosis induced by atiprimod. 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. Azaspirane significantly inhibited growth and induced caspase-mediated apoptosis in drug-sensitive and drug-resistant MM cell lines, as well as patient MM cells. We here characterize the effect of atiprimod on human multiple myeloma (MM) cells. On Arch, the package name is lib32-gnutls.Azaspirane ( N-N-diethyl-8,8-dipropyl-2-azaspiro 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. If the authorization process fails with the error "Adobe Digital Editions could not connect to the activation server," make sure you have libgnutls installed. Use winetricks to install corefonts and dotnet40 (both are required for ADE to work). Alternatively, you may download version 4.5.0 here.įirst of all, you must be running a 32-bit prefix. The installer of the latest version (4.5.7) does not start, but you can extract the files directly with p7zip. Arch Linux x86_64 (with samba and lib32-gnutls).Opening books (DRM-protected and regular).Fulfilling DRM-protected books with ACSM files.Some display glitches are to be expected, but the app is functional overall.
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