Effects of the phosphoinostitide-3′-kinase delta inhibitor, CAL-101, in combination with Bortezomib on mantle lymophma cells and exploration of its related mechanism
10.3760/cma.j.issn.0253-3766.2015.06.003
- VernacularTitle:P I3 K-p110σ抑制剂联合硼替佐米对套细胞淋巴瘤细胞增殖和凋亡的影响及其机制
- Author:
Fulian QU
1
;
Bing XIA
;
Xiaowu LI
;
Shanqi GUO
;
Le ZHANG
;
Chen TIAN
;
Yong YU
;
Yizhuo ZHANG
Author Information
1. 300060,天津医科大学肿瘤医院血液科 国家肿瘤临床医学研究中心 天津市“肿瘤防治”重点实验室
- Keywords:
Mantle cell lymphoma;
CAL-101;
Bortezomib;
Synergistic effects;
proliferation;
Apoptosis;
Cell lines
- From:
Chinese Journal of Oncology
2015;(6):412-417
- CountryChina
- Language:Chinese
-
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.
