title: [Effects of the phosphoinostitide-3'-kinase delta inhibitor, CAL-101, in combination with Bortezomib on mantle lymophma cells and exploration of its related mechanism].
abstract: OBJECTIVE
  To investigate the effect of CAL-101, a selective inhibitor of PI3Kδ, in combination with bortezomib on the proliferation and apoptosis in human mantle cell lymphoma cell lines Z138, HBL-2 and Jeko-1 in vitro, to explore its mechanisms and provide the foundation for effective treatment strategies against mantle cell lymphoma.
  
  
  METHODS
  MTT assay was applied to detect the inhibitory effects of CAL-101 and bortezomib either alone or combined on Z138, HBL-2 and Jeko-1 cells. Calcusyn software was used to analyze the synergistic cytotoxicity. Western blot was used to detect the expression of PI3K-p110σ and p-Akt, Akt, p-ERK and ERK proteins after the cells were exposed to different concentrations of CAL-101. Flow cytometry was employed to assess the apoptosis rate. NF-κB kit was used to determine the changes of location of NF-κB P65, and Western blot was applied to detect the level of caswpase-3 and the phosphorylation of Akt in different groups.
  
  
  RESULTS
  CAL-101 and BTZ inhibited the proliferation of Z138, HBL-2 and Jeko-1 cells in a dose- and time-dependent manner. CAL-101/BTZ combination induced significantly synergistic cytotoxicity in the MCL cells. The results of Western blot assay showed that CAL-101 significantly blocked the phosphorylation of Akt and ERK in the MCL cell lines. In addition, CAL-101 combined with BTZ induced pronounced apoptosis (P < 0.01). For example, after the Z138 cells exposed to the drugs for 48 h, the apoptosis rates of the control, CAL-101, BTZ and CAL-101 + BTZ groups were: (2.6 ± 1.8)%, (40.0 ± 3.0)%, (34.0 ± 1.0)%, and (67.4 ± 1.0)%, respectively; and when drug treatment was given to HBL-2 cells over 96 h, the apoptosis rates of these four cell groups were (7.4 ± 0.6)%, (30.7 ± 5.7)%, (12.0 ± 1.0)%, and (85.0 ± 4.0)%, respectively. The combination therapy contributed to the enhanced inactivity of nuclear factor-κB (NF-κB) and Akt inactivation in the MCL cell lines (P < 0.05), however, the casepase-3 activity was up-regulated.
  
  
  CONCLUSIONS
  The combination of CAL-101 and bortezomib is muchmore effective in inhibiting proliferation and promoting apoptosis of mantle cell lymphoma cell lines (Z138, HBL-2 and Jeko-1), which may be mediated through inhibiting PI3K/Akt signaling pathway and the transcription of NF-κB.
authors.affiliation: Department of Hematology, Tianjin Cancer Institute and Hospital, Tianjin 300060, China.
authors.forename: Fulian
authors.initials: F
authors.lastname: Qu
authors.affiliation: Department of Hematology, Tianjin Cancer Institute and Hospital, Tianjin 300060, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Xia
authors.affiliation: Department of Hematology, Tianjin Cancer Institute and Hospital, Tianjin 300060, China.
authors.forename: Xiaowu
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Hematology, Tianjin Cancer Institute and Hospital, Tianjin 300060, China.
authors.forename: Shanqi
authors.initials: S
authors.lastname: Guo
authors.affiliation: Department of Hematology, Tianjin Cancer Institute and Hospital, Tianjin 300060, China.
authors.forename: Le
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Hematology, Tianjin Cancer Institute and Hospital, Tianjin 300060, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Tian
authors.affiliation: Department of Hematology, Tianjin Cancer Institute and Hospital, Tianjin 300060, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Hematology, Tianjin Cancer Institute and Hospital, Tianjin 300060, China; Email: 18622221239@163.com.
authors.forename: Yizhuo
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001897:Boronic Acids; D000069286:Bortezomib / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005562:Formazans; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology*; D011719:Pyrazines; D052999:Quinazolinones / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction; D012984:Software; D013778:Tetrazolium Salts
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D000069286:Bortezomib; D053148:Caspase 3; D005562:Formazans; D016328:NF-kappa B; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011687:Purines; D011719:Pyrazines; D052999:Quinazolinones; D013778:Tetrazolium Salts; C079782:MTT formazan; C552946:idelalisib