Cancer Chemotherapy and Pharmacology

, Volume 84, Issue 6, pp 1303–1314 | Cite as

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

  • Ling LiuEmail author
  • Jingjing Chen
  • Mengyao Cao
  • Jiangang Wang
  • Shuying Wang
Original Article



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.


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


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.


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


Nitric oxide Apoptosis PABA/NO Hepatocellular carcinoma 



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).

Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmacy, Medical CollegeHenan University of Science and TechnologyLuoyangChina

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