title: [Effects of PCI-32765 and Dasatinib on the Acute Lymphoblastic Leukemic Cells and Their Mechanisms].
abstract: OBJECTIVE
  To investigate the effects of Btk inhibitor (PCI-32765) and BCR-ABL tyrosine kinase inhibitor (Dasatinib) on proliferation and apoptosis of acute lymphoblastic leukemia (ALL) cell lines (Sup-B15, RS4;11) and the possible mechanism.
  
  
  METHODS
  RS4;11 and Sup-B15 cells were treated with PCI-32765 and Dasatinib, the cell proliferation and apoptosis were detected by CCK-8, the Btk and other apoptotic proteins were detected by Western blot.
  
  
  RESULTS
  PCI-32765 could inhibit the proliferation of RS4;11 and Sup-B15 cells in a dose-dependent manner, Sup-B15 cells were more sensitive to PCI-32765 than RS4;11 cells, their IC50were 3 µmol/L and 8 µmol/L respectively, the difference between them was statistically significant (P<0.05). Dasatinib also could inhibit the proliferation of RS4;11 cells and Sup-B15 cells in a dose-dependent manner. The IC50was 5 µmol/L and 5 nmol/L, respectively, the difference between them was statistically very significant (P<0.01), and the inhibitory effect was enhanced by the combination of Damatinib with the PCI-32765(P<0.05). The cell survival rate decreased gradually in PCI-32765 or Dasatinib alone group and the combination group at the different time-point (8, 12, 24, 36, 48 and 72 h), the 2 drugs showed a synergistic effect on cells in a time-dependent manner. After being treated with PCI-32765 and Dasatinib, the RS4;11 and Sup-B15 cells showed that cell shrinkage, increase of cytoplasmic density, nuclear pyknosis, deviation and karyorrhexis, and increase of the apoptotic cells in the combination group, while the promotive effect of low dosage dasatinib on apoptosis of RS4;11 cells was not strong. PCI-32765 and Dasatinib could decrease the expression and activity of BCR-ABL, Btk, Lyn, Src in Sup-B15 and RS4;11 cells.
  
  
  CONCLUSIONS
  PCI-32765 or Dasatinib can inhibit the proliferation and induce the apoptosis of Sup-B15 and RS4;11 cells, PCI-32765 and Dasatinib displayed the synergistic effects. The possible mechanism may be related with the blocking of B cell receptor(BCR) signal pathway, thereby inhibiting the cell proliferation and promoting the cell apoptosis.
authors.affiliation: Department of Hematology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an 223300, Jiangsu Province, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Department of Hematology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an 223300, Jiangsu Province, China.
authors.forename: Shan-Dong
authors.initials: SD
authors.lastname: Tao
authors.affiliation: Department of Hematology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an 223300, Jiangsu Province, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Hematology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an 223300, Jiangsu Province, China.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Ma
authors.affiliation: Department of Hematology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an 223300, Jiangsu Province, China.
authors.forename: Zheng-Mei
authors.initials: ZM
authors.lastname: He
authors.affiliation: Department of Hematology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an 223300, Jiangsu Province, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Hematology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an 223300, Jiangsu Province, China.
authors.forename: Zhi-Kui
authors.initials: ZK
authors.lastname: Deng
authors.affiliation: Department of Hematology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an 223300, Jiangsu Province, China. E-mail: yuliang1965@gmail.com.
authors.forename: Liang
authors.initials: L
authors.lastname: Yu
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D000069439:Dasatinib / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D010880:Piperidines; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D016044:Fusion Proteins, bcr-abl; D000225:Adenine; D000069439:Dasatinib