title: Synergistic suppression of the PI3K inhibitor CAL-101 with bortezomib on mantle cell lymphoma growth.
abstract: OBJECTIVE
  To investigate the effects of CAL-101, particularly when combined with bortezomib (BTZ) on mantle cell lymphoma (MCL) cells, and to explore its relative mechanisms.
  
  
  METHODS
  MTT assay was applied to detect the inhibitory effects of different concentrations of CAL-101. MCL cells were divided into four groups: control group, CAL-101 group, BTZ group, and CAL-101/BTZ group. The expression of PI3K-p110σ, AKT, ERK, p-AKT and p-ERK were detected by Western blot. The apoptosis rates of CAL-101 group, BTZ group, and combination group were detected by flow cytometry. The location changes of nuclear factor kappa-B (NF-κB) of 4 groups was investigated by NF-κB Kit exploring. Western blot was applied to detect the levels of caspase-3 and the phosphorylation of AKT in different groups.
  
  
  RESULTS
  CAL-101 dose- and time-dependently induced reduction in MCL cell viability. CAL-101 combined with BTZ enhanced the reduction in cell viability and apoptosis. Western blot analysis showed that CAL-101 significantly blocked the PI3K/AKT and ERK signaling pathway in MCL cells. The combination therapy contributed to the inactivation of NF-κB and AKT in MCL cell lines. However, cleaved caspase-3 was up-regulated after combined treatment.
  
  
  CONCLUSIONS
  Our study showed that PI3K/p110σ is a novel therapeutic target in MCL, and the underlying mechanism could be the blocking of the PI3K/AKT and ERK signaling pathways. These findings provided a basis for clinical evaluation of CAL-101 and a rationale for its application in combination therapy, particularly with BTZ.
authors.affiliation: 1 Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China ; 2 Department of Medical Oncology, Kaifeng Central Hospital, Kaifeng 475000, China ; 3 Department of Geriatric Hematology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Fu-Lian
authors.initials: FL
authors.lastname: Qu
authors.affiliation: 1 Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China ; 2 Department of Medical Oncology, Kaifeng Central Hospital, Kaifeng 475000, China ; 3 Department of Geriatric Hematology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Xia
authors.affiliation: 1 Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China ; 2 Department of Medical Oncology, Kaifeng Central Hospital, Kaifeng 475000, China ; 3 Department of Geriatric Hematology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Su-Xia
authors.initials: SX
authors.lastname: Li
authors.affiliation: 1 Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China ; 2 Department of Medical Oncology, Kaifeng Central Hospital, Kaifeng 475000, China ; 3 Department of Geriatric Hematology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Tian
authors.affiliation: 1 Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China ; 2 Department of Medical Oncology, Kaifeng Central Hospital, Kaifeng 475000, China ; 3 Department of Geriatric Hematology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Hong-Liang
authors.initials: HL
authors.lastname: Yang
authors.affiliation: 1 Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China ; 2 Department of Medical Oncology, Kaifeng Central Hospital, Kaifeng 475000, China ; 3 Department of Geriatric Hematology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: 1 Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China ; 2 Department of Medical Oncology, Kaifeng Central Hospital, Kaifeng 475000, China ; 3 Department of Geriatric Hematology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Ya-Fei
authors.initials: YF
authors.lastname: Wang
authors.affiliation: 1 Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China ; 2 Department of Medical Oncology, Kaifeng Central Hospital, Kaifeng 475000, China ; 3 Department of Geriatric Hematology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yu
authors.affiliation: 1 Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China ; 2 Department of Medical Oncology, Kaifeng Central Hospital, Kaifeng 475000, China ; 3 Department of Geriatric Hematology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Yi-Zhuo
authors.initials: YZ
authors.lastname: Zhang
keywords: CAL-101; bortezomib (BTZ); mantle cell lymphoma (MCL); phosphatidylinositol-3-kinase (PI3K)