Effects of the phosphoinostitide-3'-kinase delta inhibitor, CAL-101, in combination with Bortezomib on mantle lymophma cells and exploration of its related mechanism.
- Author:
Fulian QU
1
;
Bing XIA
1
;
Xiaowu LI
1
;
Shanqi GUO
1
;
Le ZHANG
1
;
Chen TIAN
1
;
Yong YU
1
;
Yizhuo ZHANG
2
;
Email: 18622221239@163.COM.
Author Information
- Publication Type:Journal Article
- MeSH: Antineoplastic Agents; pharmacology; Antineoplastic Combined Chemotherapy Protocols; pharmacology; Apoptosis; drug effects; Blotting, Western; Boronic Acids; Bortezomib; pharmacology; Caspase 3; metabolism; Cell Line, Tumor; Cell Proliferation; drug effects; Class Ia Phosphatidylinositol 3-Kinase; antagonists & inhibitors; Dose-Response Relationship, Drug; Drug Synergism; Formazans; Humans; Lymphoma, Mantle-Cell; drug therapy; pathology; MAP Kinase Signaling System; drug effects; NF-kappa B; metabolism; Neoplasm Proteins; metabolism; Phosphatidylinositol 3-Kinases; metabolism; Phosphorylation; drug effects; Proto-Oncogene Proteins c-akt; metabolism; Purines; administration & dosage; pharmacology; Pyrazines; Quinazolinones; administration & dosage; pharmacology; Signal Transduction; Software; Tetrazolium Salts
- From: Chinese Journal of Oncology 2015;37(6):412-417
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVETo 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.
METHODSMTT 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.
RESULTSCAL-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.
CONCLUSIONSThe 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.
