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Cilostazol Induces Apoptosis and Inhibits Proliferation of Hepatocellular Carcinoma Cells by Activating AMPK

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Abstract

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and one of the leading causes of cancer-related death. Cilostazol, an antiplatelet drug, elicits anticancer effects on human squamous cell carcinoma and colon cancer cells. We previously reported that cilostazol protects normal mature hepatocytes from alcohol-induced apoptotic cell death. In addition, cilostazol stimulates liver regeneration after hepatectomy. Therefore, this study evaluated whether cilostazol elicits pro- or anti-proliferative effects on HCC using Hep3B and SK-Hep1 cells. Cilostazol inhibited proliferation of HCC cells by inducing apoptosis. Additionally, cilostazol induced G0/G1 cell cycle arrest and decreased expression of cyclin D1 and proliferating cell nuclear antigen. Activation of AMP-activated protein kinase (AMPK) and inhibition of extracellular signal-regulated kinase (ERK) and AKT signaling were associated with the anti-proliferative effect of cilostazol. LY294002 and PD98059, inhibitors of AKT and ERK, respectively, enhanced the anti-proliferative effect of cilostazol. By contrast, inhibition of AMPK using compound C or AMPK-targeting siRNA abolished the anti-proliferative effect of cilostazol. Moreover, AMPK inhibition reversed the down-regulation of AKT/EKR induced by cilostazol, indicating negative cross-talk between AMPK and AKT/ERK. These findings provide evidence that cilostazol exerts anti-tumor activity in HCC by counter-regulating AMPK and AKT/ERK signaling. Taken together, our findings suggest that cilostazol may provide clinical benefits in HCC patients by selectively targeting HCC cells without interfering with liver function.

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Acknowledgement

This work was supported by research grants from Daegu Catholic University in 2018 (No.20185003).

The authors have no potential conflicts of interest to disclose. Neither ethical approval nor informed consent was required for this study.

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  1. These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, School of Medicine, Catholic University of Daegu, Daegu, 42472, Korea

    Kyeong Hwa Sim, Bo-Hyun Choi & Youn Ju Lee

  2. Deparment of Physiology, School of Medicine, Yeungnam University, Daegu, 42415, Korea

    Mi-Sun Shu & Jong-Yeon Kim

  3. Deparment of Pharmacology, School of Medicine, Dongguk University, Gyeongju, 38066, Korea

    Soyoung Kim

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  1. Kyeong Hwa Sim
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Sim, K.H., Shu, MS., Kim, S. et al. Cilostazol Induces Apoptosis and Inhibits Proliferation of Hepatocellular Carcinoma Cells by Activating AMPK. Biotechnol Bioproc E 26, 776–785 (2021). https://doi.org/10.1007/s12257-021-0002-8

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