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  • Title: NO donor inhibits proliferation and induces apoptosis by targeting PI3K/AKT/mTOR and MEK/ERK pathways in hepatocellular carcinoma cells.
    Author: Liu L, Chen J, Cao M, Wang J, Wang S.
    Journal: Cancer Chemother Pharmacol; 2019 Dec; 84(6):1303-1314. PubMed ID: 31555866.
    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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