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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

SIMPLE SUMMARY: 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...

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Autores principales: Chen, Cheng-Hsien, Hsu, Fei-Ting, Chen, Wei-Lung, Chen, Jiann-Hwa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123296/
https://www.ncbi.nlm.nih.gov/pubmed/33922992
http://dx.doi.org/10.3390/cancers13092066
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author Chen, Cheng-Hsien
Hsu, Fei-Ting
Chen, Wei-Lung
Chen, Jiann-Hwa
author_facet Chen, Cheng-Hsien
Hsu, Fei-Ting
Chen, Wei-Lung
Chen, Jiann-Hwa
author_sort Chen, Cheng-Hsien
collection PubMed
description SIMPLE SUMMARY: 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 Ca(2+), 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. ABSTRACT: 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.
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spelling pubmed-81232962021-05-16 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 Chen, Cheng-Hsien Hsu, Fei-Ting Chen, Wei-Lung Chen, Jiann-Hwa Cancers (Basel) Article SIMPLE SUMMARY: 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 Ca(2+), 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. ABSTRACT: 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. MDPI 2021-04-25 /pmc/articles/PMC8123296/ /pubmed/33922992 http://dx.doi.org/10.3390/cancers13092066 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Chen, Cheng-Hsien
Hsu, Fei-Ting
Chen, Wei-Lung
Chen, Jiann-Hwa
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123296/
https://www.ncbi.nlm.nih.gov/pubmed/33922992
http://dx.doi.org/10.3390/cancers13092066
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