Synergistic suppression of the PI3K inhibitor CAL-101 with bortezomib on mantle cell lymphoma growth

• Published in: Cancer biology & medicine Vol. 12; no. 4; pp. 401 - 408
• Main Authors: Qu, Fu-Lian, Xia, Bing, Li, Su-Xia, Tian, Chen, Yang, Hong-Liang, Li, Qian, Wang, Ya-Fei, Yu, Yong, Zhang, Yi-Zhuo
• Format: Journal Article
• Language: English
• Published: China Chinese Anti-Cancer Association (CACA), Cancer Biology & Medicine 01.12.2015; 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%Department of Geriatric Hematology, Chinese PLA General Hospital, Beijing 100853, China; Chinese Anti-Cancer Association; China Anti-Cancer Association
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Apoptosis; blot分析; Bortezomib; bortezomib (BTZ); CAL-101; Cancer therapies; Caspase; Caspase-3; Cell cycle; Cell lines; Drug dosages; Experiments; Flow cytometry; Kinases; Leukemia; Lymphoma; Mantle cell lymphoma; mantle cell lymphoma (MCL); Multiple myeloma; NF-κB; NF-κB protein; Original; phosphatidylinositol-3-kinase (PI3K); Phosphorylation; Proteins; Signal transduction; Software; Statistical analysis; Therapeutic applications; 协同; 抑制剂; 淋巴瘤; 细胞凋亡; United States > US; mantle cell lymphoma (MCL); CAL-101; bortezomib (BTZ); phosphatidylinositol-3-kinase (PI3K)
• ISSN: 2095-3941; 2095-3941
• DOI: 10.7497/j.issn.2095-3941.2015.0013

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. Conclusion： 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.