title: Novel phosphatidylinositol 3-kinase inhibitor BKM120 enhances the sensitivity of multiple myeloma to bortezomib and overcomes resistance.
abstract: Proteasome inhibitor bortezomib has proven efficacy against multiple myeloma. However, bortezomib activates the phosphatidylinositol 3-kinase/AKT (PI3K/AKT) pathway (which is essential to the development of myeloma), often resulting in drug resistance and disease recurrence. The addition of BKM120 significantly enhanced the apoptotic effects of bortezomib in both bortezomib-sensitive and bortezomib-resistant cells. Treatment with bortezomib alone increased the phosphorylation of AKT (P-AKT), whereas the addition of BKM120 markedly downregulated P-AKT in both bortezomib-sensitive and bortezomib-resistant cells. The clinical relevance of combined treatment with bortezomib and BKM120 was investigated in a xenograft mouse model and in myeloma patients, and the synergy of the combination was confirmed. In conclusion, the addition of BKM120 enhanced the sensitivity of myeloma cells to bortezomib.
authors.affiliation: a Department of Hematology , Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine , Shanghai , China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Yu
authors.affiliation: a Department of Hematology , Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine , Shanghai , China.
authors.forename: Yubao
authors.initials: Y
authors.lastname: Chen
authors.affiliation: a Department of Hematology , Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine , Shanghai , China.
authors.forename: Rufang
authors.initials: R
authors.lastname: Xiang
authors.affiliation: a Department of Hematology , Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine , Shanghai , China.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Xu
authors.affiliation: a Department of Hematology , Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine , Shanghai , China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: a Department of Hematology , Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine , Shanghai , China.
authors.forename: Jia
authors.initials: J
authors.lastname: Tong
authors.affiliation: a Department of Hematology , Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine , Shanghai , China.
authors.forename: Nan
authors.initials: N
authors.lastname: Zhang
authors.affiliation: b Hongqiao International Institute of Medicine, Shanghai Tongren Hospital , Shanghai , China.|c Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education , School of Medicine, Shanghai Jiao Tong University , Shanghai , China.
authors.forename: Yingli
authors.initials: Y
authors.lastname: Wu
authors.affiliation: a Department of Hematology , Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine , Shanghai , China.
authors.forename: Hua
authors.initials: H
authors.lastname: Yan
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000069286:Bortezomib / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D009025:Morpholines / Q000494:pharmacology*; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000631:Aminopyridines; D000069286:Bortezomib; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C571178:NVP-BKM120
keywords: BKM120; bortezomib; drug resistance; mouse model; multiple myeloma cells