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NO donor inhibits proliferation and induces apoptosis by targeting PI3K/AKT/mTOR and MEK/ERK pathways in hepatocellular carcinoma cells

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Abstract

Background

PABA/NO, O2-{2,4-dinitro-5-[4-(N-methylamino) benzoyloxy] phenyl} 1-(N, N-dimethylamino) diazen-1-ium-1,2-diolate, is a diazeniumdiolate-based NO-donor prodrug that releases exogenous nitric oxide at high concentrations to induce apoptosis in many tumor cell lines.

Purpose

This study aimed to determine the effects of PABA/NO on hepatocellular carcinoma proliferation and apoptosis induction both in vitro and in vivo experiments.

Results

PABA/NO dramatically inhibited the growth of Bel-7402 hepatocellular carcinoma cells and significantly induced apoptosis in a concentration-dependent manner, accompanied by down-regulation of Bcl-2 and Bcl-xL, up-regulation of Bax and Bad, release of Cyt c and activation of cleaved-caspase-9/3 and cleaved-PARP, which were related to suppressing PI3K/AKT/mTOR and MEK/ERK signaling pathways. LY294002 (a PI3K inhibitor) and U0126 (an ERK inhibitor) prior to PABA/NO were found to synergistically enhance PABA/NO-induced apoptosis. Carboxy-PTIO as a NO scavenger obviously attenuated PABA/NO-induced apoptosis. Additionally, H22 tumor-bearing mice experiments demonstrated that PABA/NO exerted good anti-tumor effects via reducing tumor volume, tumor weight and decreasing the expression of CD34. Furthermore, PABA/NO treatment strongly inhibited the phosphorylation of PI3K/AKT/mTOR and MEK/ERK signaling pathways in H22 hepatocellular carcinoma tissues.

Conclusions

PABA/NO induced apoptosis through inhibition of PI3K/Akt/mTOR and MEK/ERK pathway in hepatocellular carcinoma cells.

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Funding

This study was funded by the National Natural Science Foundation of China (No. 81502627) and the Young Backbone Teachers Assistance Scheme of Henan Province Colleges and Universities (No. 2016GGJS-065).

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Authors and Affiliations

  1. Department of Pharmacy, Medical College, Henan University of Science and Technology, 263 Kaiyuan Avenue, Luoyang, 471023, China

    Ling Liu, Jingjing Chen, Mengyao Cao, Jiangang Wang & Shuying Wang

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  1. Ling Liu
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  2. Jingjing Chen
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  3. Mengyao Cao
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Correspondence to Ling Liu.

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Liu, L., Chen, J., Cao, M. et al. NO donor inhibits proliferation and induces apoptosis by targeting PI3K/AKT/mTOR and MEK/ERK pathways in hepatocellular carcinoma cells. Cancer Chemother Pharmacol 84, 1303–1314 (2019). https://doi.org/10.1007/s00280-019-03965-5

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