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Article

Induction of Apoptosis, Inhibition of MCL-1, and VEGF-A Expression Are Associated with the Anti-Cancer Efficacy of Magnolol Combined with Regorafenib in Hepatocellular Carcinoma

by 1,†, 2,†, 3,4,† and 3,4,*
1
Surgical Department of Show Chwan Memorial Hospital, Changhua 500, Taiwan
2
Department of Biological Science and Technology, China Medical University, Taichung 406, Taiwan
3
Department of Emergency Medicine, Cathay General Hospital, Taipei 106, Taiwan
4
School of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
*
Author to whom correspondence should be addressed.
Authors contributed equally.
Academic Editors: Patrycja Nowak-Sliwinska and Arjan W. Griffioen
Cancers 2021, 13(9), 2066; https://doi.org/10.3390/cancers13092066
Received: 2 March 2021 / Revised: 20 April 2021 / Accepted: 21 April 2021 / Published: 25 April 2021
(This article belongs to the Special Issue Combination Therapies in Cancers)
The synergistic inhibition of hepatocellular carcinoma growth was induced by administering magnolol together with regorafenib, instead of each treatment individually. Hepatocellular carcinoma (HCC) cells were sensitized to regorafenib through the inhibition of the expression of both vascular endothelial growth factor A (VEGF-A) and myeloid cell leukemia 1 (MCL-1) by siRNA. Moreover, the regorafenib-induced suppression of VEGF-A and MCL-1 at the protein level was enhanced by magnolol. Extrinsic (expression of FAS, FAS-L, and cleaved-caspase-8) and intrinsic apoptotic signaling (ROS production, the accumulation of Ca2+, the loss of △ψm, and the nuclear translocation of AIF), and DNA damage were all effectively increased by regorafenib combined with magnolol. In addition, a superior inhibition of metastasis was triggered by the combination of regorafenib and magnolol. In sum, the enhancement of apoptosis induction and the suppression of the expression of VEGF-A and MCL-1 were associated with the anti-cancer efficacy of magnolol combined with regorafenib in HCC.
While regorafenib was approved for the treatment of advanced HCC in 2017, with a partial response and survival benefit; other combination agents to facilitate the efficacy of regorafenib still need to be explored. Magnolol is a potential natural anti-tumor compound for many types of cancers. Combination indexes calculated on the basis of both in vitro and in vivo models have indicated a synergistic effect of the combination of regorafenib and magnolol. The overexpression of the VEGF-A protein significantly diminished regorafenib’s inhibition of cell viability, while the transient knockdown of VEGF-A by siRNA effectively sensitized HCC cells to regorafenib. In addition, the inhibition of MCL-1 by siRNA combined with regorafenib allowed for a significantly greater inhibition of cell growth, compared to regorafenib alone. A lower protein expression level for VEGF-A and MCL-1 was found for the combination treatment of HCC in vitro and in vivo. A superior metastasis inhibition was also found in the combination group, as compared to the single-treatment groups, using a transwell assay, wound healing assay, and Western blotting. The caspase-dependent and -independent and DNA damage effects, as determined by flow cytometry and a comet assay, were increased by the combination therapy. Taken together, magnolol sensitized HCC to regorafenib, which was correlated with the reduction of VEGF-A and MCL-1 and the induction of apoptosis. View Full-Text
Keywords: magnolol; regorafenib; apoptosis; MCL-1; VEGF-A; hepatocellular carcinoma magnolol; regorafenib; apoptosis; MCL-1; VEGF-A; hepatocellular carcinoma
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MDPI and ACS Style

Chen, C.-H.; Hsu, F.-T.; Chen, W.-L.; Chen, J.-H. Induction of Apoptosis, Inhibition of MCL-1, and VEGF-A Expression Are Associated with the Anti-Cancer Efficacy of Magnolol Combined with Regorafenib in Hepatocellular Carcinoma. Cancers 2021, 13, 2066. https://doi.org/10.3390/cancers13092066

AMA Style

Chen C-H, Hsu F-T, Chen W-L, Chen J-H. Induction of Apoptosis, Inhibition of MCL-1, and VEGF-A Expression Are Associated with the Anti-Cancer Efficacy of Magnolol Combined with Regorafenib in Hepatocellular Carcinoma. Cancers. 2021; 13(9):2066. https://doi.org/10.3390/cancers13092066

Chicago/Turabian Style

Chen, Cheng-Hsien, Fei-Ting Hsu, Wei-Lung Chen, and Jiann-Hwa Chen. 2021. "Induction of Apoptosis, Inhibition of MCL-1, and VEGF-A Expression Are Associated with the Anti-Cancer Efficacy of Magnolol Combined with Regorafenib in Hepatocellular Carcinoma" Cancers 13, no. 9: 2066. https://doi.org/10.3390/cancers13092066

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