Therefore; the present study investigated the effect of the ASA and BTZ combination on the level of survivin. As shown inFig. phosphorylated AKT (p-AKT) and survivin, whereas BTZ alone augmented the levels YHO-13177 of p-AKT and survivin. Of note, ASA markedly decreased the upregulation of p-AKT and survivin induced by BTZ. Treatment with ASA+BTZ significantly suppressed the level of Bcl-2, compared with either agent only. ASA may potentiate the antimyeloma activity of BTZ against myeloma cells via suppression of AKT phosphorylation, survivin and Bcl-2, indicating the potential of ASA+BTZ in treating MM, particularly for cases of BTZ-refractory/relapsed MM. Keywords: aspirin, bortezomib, multiple myeloma, survivin, B cell lymphoma-2, AKT phosphorylation == Introduction == Multiple myeloma (MM) is a malignant neoplasia of plasma cells, which accounts for ~10% of all types of hematological cancer. According to the latest statistics, the annual incidence of MM was reported to be 20, 450 cases and the mortality rate for MM was 11, 090 cases/year in the USA in 2013 (1). In addition , MM has evolved as one of the major diseases affecting the aging population in China (2). At present, MM is the second most prevalent hematological malignancy following non-Hodgkin’s lymphoma (2). Even with the introduction of immunmodulators, including thalidomide and lenalidomide, and proteasome inhibitors, including bortezomib (BTZ), over the last decade, the 5-year survival rate of patients in the USA with MM is only 42% (1). In addition , almost all patients with MM undergo relapse and refractory disease, predominantly due to drug resistance (3). Until now, MM remains an incurable disorder among hematological malignancies. YHO-13177 Patients with MM are at enhanced risk of thromboembolism due to disease-specific and treatment-specific risk factors, particularly when treated with thalidomide and lenalidomide (4, 5). Thus, the prevention of thrombosis has become important in cases of MM. At present, no significant differences have been observed among the use of aspirin (ASA), low-dose warfarin and low-molecular weight heparin in thromboprophylaxis (6). ASA may be the optimum candidate to YHO-13177 prevent thromboembolism in patients with MM due to its merits in method of administration, security and cost without the requirement for regular coagulation monitoring (7). ASA continues to be widely used intended for thromboprophylaxis in patients with MM, particularly in cases treated with thalidomide or lenalidomide combinations. An increasing number of studies have demonstrated that ASA possesses antineoplastic actions against a wide range of solid tumor types, including esophageal, breast, lung and gastric cancer, and colon cancer in particular (812). Currently, the Mouse monoclonal to IKBKB underlying anticancer mechanisms of ASA have been ascribed to the inhibition of nuclear element (NF)-kB, and the induction of apoptosis by caspase activation, interruption of extracellular signal-regulated kinase and epidermal growth factor receptor in various types of cancer (1317). Our previous study found that ASA exerted antiproliferative and pro-apoptotic activitiesin vivoandin vitrovia the upregulation of B cell lymphoma-2 (Bcl-2)-associated X protein (Bax), and the suppression of Bcl-2 and vascular endothelial growth factor (18). The antimyeloma effect of BTZ, the first proteasome inhibitor to be approved by the Food and Drug Supervision of USA in 2003, is well-recognized. At present, BTZ has become the foundation of first- and second-line treatment in MM. The major mechanisms underlying the action of BTZ in MM include inhibition from the activation of NF-kB, upregulation of pro-apoptotic Noxa and the subsequent downregulation of anti-apoptotic Bcl-2 (19). However , the increasing supervision of BTZ is associated with the development of drug resistance (20). There have been a number of explanations intended for the insensitivity to BTZ, including proteasome subunit 5 mutation, insulin growth factor-1 and the differentiation status of myeloma cells (2123). The activation of AKT and upregulation of survivin induced by BTZ itself are the primary factors involved in the development of resistance to BTZ in MM (24). Coincidentally, survivin, Bcl-2 and AKT have been confirmed to be the focuses on of ASA in gastric, cervical and ovarian.