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

• Main Authors: Fu-Lian Qu, Bing Xia, Su-Xia Li, Chen Tian, Hong-Liang Yang, Qian Li, Ya-Fei Wang, Yong Yu, Yi-Zhuo Zhang
• Format: Article
• Language: English
• Published: China Anti-Cancer Association 2015-12-01
• Series: Cancer Biology & Medicine
• Subjects: CAL-101; bortezomib (BTZ); phosphatidylinositol-3-kinase (PI3K); mantle cell lymphoma (MCL)
• Online Access: http://www.cancerbiomed.org/index.php/cocr/article/view/894
• ISSN: 2095-3941; 2095-3941

<b>Objective:</b>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.<br/><b>Methods:</b>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-p110&#963;, 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.<br/><b>Results:</b>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.<br/><b>Conclusion:</b>Our study showed that PI3K/p110&#963; 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.