title: [Effect of PI3Kδ inhibitor CAL-101 on myeloma cell lines and preliminary study of synergistic effects with other new drugs].
abstract: OBJECTIVE
  To investigate the proliferation inhibitory role and mechanism of PI3Kδ inhibitor CAL-101 on multiple myeloma (MM) cells, and to provide new therapeutic options for MM treatment.
  
  
  METHODS
  MM cell lines U266 and RPMI8226 cells were treated with various concentrations of CAL-101. MTT assay and CalcuSyn software were performed to determine the inhibitory effect of CAL-101 and the synergistic effect with PCI- 32765, SAHA (suberoylanilide hydroxamic acid), BTZ (Bortezomib) on MM cells. The protein expression level of p-AKT, p-ERK, AKT, ERK and PI3Kδ processed by CAL-101 were analyzed by Western blot.
  
  
  RESULTS
  CAL-101 at concentration of 15, 20, 25, 30 and 40 μmol/L could induce significant dose-dependent proliferation inhibition on U266 cells after treatment for 48 hours. The cell proliferation inhibition rates were (33.54 ± 1.23)%, (41.72 ± 1.78)%, (53.67 ± 2.01)%, (68.97 ± 2.11)% and (79.25 ± 1.92)%, respectively. Similar results were found in RPMI8226 cell line. Western blots showed high expression level of p-AKT, p-ERK, AKT, ERK and PI3Kδ in cell lines and MM primary cells. p-AKT and p-ERK protein expression levels were down-regulated significantly by CAL-101 treatment. Synergistic effect has been verified between CAL-101 and PCI-32765, SAHA and Bortezomib in U266 cell line, and PCI-32765, Bortezomib in RPMI8226 cell line with CI values less than 1.
  
  
  CONCLUSIONS
  CAL-101 could inhibit proliferation of MM cell lines. High levels of p-AKT, p-ERK, AKT, ERK and PI3Kδ protein expression were observed in both cell lines and primary cells. Down-regulation of p-AKT and p-ERK probably related with the mechanism of CAL-101 in MM cell proliferation inhibition. CAL-101 has significant synergistic effect with PCI-32765, SAHA and BTZ.
authors.affiliation: Department of Hematology, Tianjin Medical University Cancer Institute and Hospital. Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Hematology, Tianjin Medical University Cancer Institute and Hospital. Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Xia
authors.affiliation: Department of Hematology, Tianjin Medical University Cancer Institute and Hospital. Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Fulian
authors.initials: F
authors.lastname: Qu
authors.affiliation: Department of Hematology, Tianjin Medical University Cancer Institute and Hospital. Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Yuan
authors.affiliation: Department of Hematology, Tianjin Medical University Cancer Institute and Hospital. Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Shanqi
authors.initials: S
authors.lastname: Guo
authors.affiliation: Department of Hematology, Tianjin Medical University Cancer Institute and Hospital. Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Weipeng
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Hematology, Tianjin Medical University Cancer Institute and Hospital. Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Hematology, Tianjin Medical University Cancer Institute and Hospital. Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Hematology, Tianjin Medical University Cancer Institute and Hospital. Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Yafei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Hematology, Tianjin Medical University Cancer Institute and Hospital. Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Yizhuo
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D001897:Boronic Acids; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation; D006801:Humans; D009101:Multiple Myeloma / Q000473:pathology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology*; D011719:Pyrazines; D011720:Pyrazoles; D011743:Pyrimidines; D052999:Quinazolinones / Q000494:pharmacology*
chemical_list: D001897:Boronic Acids; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011687:Purines; D011719:Pyrazines; D011720:Pyrazoles; D011743:Pyrimidines; D052999:Quinazolinones; C551803:ibrutinib; D000069286:Bortezomib; D000225:Adenine; C552946:idelalisib