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Open AccessArticle

Protein Kinase B Inactivation Is Associated with Magnolol-Enhanced Therapeutic Efficacy of Sorafenib in Hepatocellular Carcinoma In Vitro and In Vivo

by Jiann-Hwa Chen 1,2, I-Tsang Chiang 3,4,5,*,† and Fei-Ting Hsu 6,*,†
Department of Emergency Medicine, Cathay General Hospital, Taipei 280, Taiwan
School of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
Department of Radiation Oncology, Show Chwan Memorial Hospital, Changhua 500, Taiwan
Department of Radiation Oncology, Chang Bing Show Chwan Memorial Hospital, Changhua 505, Taiwan
Department of Medical Imaging and Radiological Sciences, Central Taiwan University of Science and Technology, Taichung 406, Taiwan
Department of Biological Science and Technology, China Medical University, Taichung 404, Taiwan
Authors to whom correspondence should be addressed.
These authors contributed equally to this paper.
Cancers 2020, 12(1), 87;
Received: 12 July 2019 / Revised: 3 December 2019 / Accepted: 20 December 2019 / Published: 30 December 2019
(This article belongs to the Special Issue Hepatocellular Cancer Treatment)
Although sorafenib, an oral multikinase inhibitor, was approved as a treatment drug of advance hepatocellular carcinoma (HCC), treatment efficacy still requires improvement. Searching for the adjuvant reagent for enhancing sorafenib efficacy remains as a critical issue. Sorafenib has been proved to suppress extracellular signal-regulated kinases (ERK) in HCC; however, protein kinase B (AKT) was not affected by it. Targeting AKT in combination with sorafenib could be an important breakthrough point of HCC treatment. Many herbal compounds and composite formulas have been shown to enhance anti-HCC activity of sorafenib. Magnolol is a bioactive compound extracted from the bark of the Magnolia officinalis and has been shown to induce apoptosis and inhibit cell invasion in HCC in vitro. However, whether magnolol sensitizes HCC to sorafenib is ambiguous. In this study, we indicated that magnolol significantly enhanced sorafenib-diminished tumor cell growth, expression of anti-apoptotic proteins, and migration/invasion ability compared to sorafenib alone. Magnolol significantly boosted sorafenib-induced extrinsic/intrinsic dependent apoptosis pathways in HCC. Notably sorafenib could not reduce protein level of AKT (Ser473), but expression of AKT (Ser473) was significantly decreased by magnolol or magnolol combined with sorafenib. LY294002 as specific AKT inhibitor was used to confirm that AKT inactivation may promote anticancer effect of sorafenib. Taken together, AKT inhibition is associated with magnolol-enhanced the therapeutic effect of sorafenib in HCC. We suggested magnolol as the potential adjuvant which may enhance therapeutic benefits of sorafenib in patients with HCC. View Full-Text
Keywords: magnolol; sorafenib; AKT; hepatocellular carcinoma magnolol; sorafenib; AKT; hepatocellular carcinoma
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MDPI and ACS Style

Chen, J.-H.; Chiang, I.-T.; Hsu, F.-T. Protein Kinase B Inactivation Is Associated with Magnolol-Enhanced Therapeutic Efficacy of Sorafenib in Hepatocellular Carcinoma In Vitro and In Vivo. Cancers 2020, 12, 87.

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