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

• Published in: Cancers 2021-04, Vol.13 (9), p.2066
• Main Authors: Chen, Cheng-Hsien, Hsu, Fei-Ting, Chen, Wei-Lung, Chen, Jiann-Hwa
• Format: Article
• Language: English
• Subjects: Antibodies; Apoptosis; Apoptosis-inducing factor; Calcium; Caspase-8; Cell adhesion & migration; Cell cycle; Cell viability; Comet assay; Deoxyribonucleic acid; DNA; DNA damage; Flow cytometry; Hepatocellular carcinoma; Herbal medicine; Kinases; Liver cancer; Mcl-1 protein; Metastases; Metastasis; Nuclear transport; Proteins; siRNA; Vascular endothelial growth factor; Western blotting; Wound healing
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers13092066

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.