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. 2022 Feb 14;13(2):146.
doi: 10.1038/s41419-022-04583-5.

The synergistic antitumor effect of IL-6 neutralization with NVP-BEZ235 in hepatocellular carcinoma

Yao Wang #  1 , Xiaolong Miao #  2 , Yuancong Jiang #  2 , Zelai Wu  2 , Xuhang Zhu  3 , Han Liu  2 , Xiaoying Wu  4 , Jinzhen Cai  5   6 , Xianfeng Ding  7 , Weihua Gong  8   9
Affiliations

The synergistic antitumor effect of IL-6 neutralization with NVP-BEZ235 in hepatocellular carcinoma

Yao Wang et al. Cell Death Dis. .

Abstract

Hepatocellular carcinoma (HCC) still ranks among the top cancers worldwide with high incidence and mortality VSports手机版. Due to abnormal activation of the PI3K/AKT/mTOR signalling pathway in HCC, targeting this pathway represents a potential therapeutic strategy. NVP-BEZ235 is a novel dual-targeted ATP-competitive PI3K/mTOR inhibitor that has shown effective antitumor effects. In this study, we found that interleukin-6 (IL-6) was significantly increased after exposure to NVP-BEZ235, and we proposed a treatment in which an anti-IL-6 antibody was combined with NVP-BEZ235 for HCC. In vitro results revealed that targeted inhibition of IL-6 potentiated the antitumor effects of NVP-BEZ235 in HCC cells. The mechanism might be attributed to their synergistic inhibitory activity on the PI3K/AKT/mTOR signalling pathway. Furthermore, an in vivo study demonstrated that combined administration of NVP-BEZ235 and anti-IL-6 Ab reduced HCC tumour load more effectively than either NVP-BEZ235 or anti-IL-6 Ab treatment alone. These findings add guidance value to the analysis of HCC and provide a reference for clinical treatment. .

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1. The PI3K/AKT/mTOR pathway is active in hepatocellular carcinoma.
A Oncoprinter showed the distribution and frequency of PI3K/AKT/mTOR pathway-related gene mutations, copy number changes, and gene expression levels in liver cancer samples. B Analysis of survival differences in patients with liver cancer with PI3K/AKT/mTOR gene mutations from TCGA database (data source: https://www.cbioportal.org/).
Fig. 2
Fig. 2. NVP-BEZ235 inhibits HCC cell proliferation in a dose- and time-dependent manner.
A The proliferation rate of HepG2 cells treated with NVP-BEZ235. B The proliferation rate of Huh-7 cells treated with NVP-BEZ235. Compared to the 12 h treatment group. ns ≥ 0.05, * P < 0.05, ** P < 0.01, * P < 0.001.
Fig. 3
Fig. 3. NVP-BEZ235 increases the expression of IL-6.
A RNA-seq-derived transcript analysis of NVP-BEZ235-induced genes in HepG2 cells. There was at least a two-fold up- or downregulation in the gene (P < 0.01). Red indicates higher expression, and blue indicates lower expression. B IL-6 protein levels in HCC cells measured by ELISA. **p < 0.01. C Representative images of IL-6 immunohistochemical staining in the control group and NVP-BEZ235-treated group from mouse liver tumour tissues. 100×; scale bar, 100 μm. D IL‐6 protein expression in the control group and NVP-BEZ235-treated group by western blotting of mouse liver tumour tissues.
Fig. 4
Fig. 4. IL-6 blockade increases NVP-BEZ235-induced inhibition of cell viability in HCC cells.
A Cell proliferation rates of HepG2 and Huh-7 cells treated with NVP-BBEZ235, anti-IL-6 Ab, or their combination for 24 h via CCK-8 assay. B The effects of NVP-BBEZ235, anti-IL-6 Ab, or their combination on the proliferation of HepG2 and Huh-7 cells for 24 h via EdU staining assay. C Cell cycle profiles of HepG2 and Huh-7 cells treated with NVP-BBEZ235, anti-IL-6 Ab, or their combination for 24 h via flow cytometry analysis. D Cyclin D1 and cyclin E1 protein expression was detected by western blotting.
Fig. 5
Fig. 5. IL-6 blockade increases NVP-BEZ235-induced inhibition of cell migration and invasion in HCC cells.
A The scratch experiment in response to treatment of HepG2 and Huh-7 cells with NVP-BBEZ235, anti-IL-6 Ab, or their combination for 24 h. B Analysis of Transwell migration assay upon treatment of HepG2 and Huh-7 cells with NVP-BBEZ235, anti-IL-6 Ab, or their combination for 24 h. C Analysis of Transwell invasion assay upon treatment of HepG2 and Huh-7 cells with NVP-BBEZ235, anti-IL-6 Ab, or their combination for 24 h.
Fig. 6
Fig. 6. Inhibition of IL-6 combined with NVP-BEZ235 synergistically suppresses the PI3K/AKT/mTOR pathway in HCC cells.
Combined treatment inhibited activation of the PI3K/AKT/mTOR pathway in HepG2 and Huh-7 cells. The expression pattern of PI3K/AKT/mTOR pathway-associated proteins was analyzed using western blotting.
Fig. 7
Fig. 7. NVP-BEZ235 combined with IL-6 antibody effectively inhibits tumour progression and prolongs the survival time in mice with HCC.
A Scheme of the experimental procedure for NVP-BBEZ235, anti-IL-6 Ab, or the combination treatment. N-Ras/c-Myc/SB plasmids were transfected into all four groups of mice on Day 0. NVP-BBEZ235 (60 mg/kg) (or vehicle solution) was i.p. injected on Days 14-20, and anti-IL-6 Ab (or isotype IgG) was i.p. injected on Days 14, 16, and 18. All mice were euthanized 6 weeks after oncogene transfection. B Gross appearances of livers and H&E-stained liver sections in mice treated with NVP-BBEZ235, anti-IL-6 Ab, or their combination. Magnification, 100×; scale bar, 100 μm. C–F Tumour loads were evaluated by LW/BW ratios, SW/BW ratios, maximum diameter of nodules, and number of tumour nodules (mm). G Left: Representative immunostaining of Ki-67 tumour areas in liver sections. Magnification, 100×; scale bar, 100 μm. Right: Quantification of Ki67+ tumour cell numbers per field. H Kaplan–Meier survival curves of overall survival of the four groups of mice. Log-rank test was performed, n = 6 per group.
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