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

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.

Deaggregation and Crystallization Inhibition by Small Amount of Polymer Addition for a Co-Amorphous Curcumin-Magnolol System

“…In the present study, co-amorphous curcumin-magnolol was designed based on their solubility/dissolution defects and potential drug combination advantages. Curcumin (CUR, Figure 1 a) and magnolol (MAG, Figure 1 b) have gained increasing interest because of their multiple biological activities (such as antioxidant, anticancer, antimicrobial, and anti-inflammatory) [ 19 , 20 , 21 , 22 , 23 ]. Moreover, the two drugs have generated combined therapeutic effects in cardiovascular diseases, Alzheimer’s disease, and neurodegenerative diseases [ 24 , 25 , 26 ].…”

Magnolol Attenuates Right Ventricular Hypertrophy and Fibrosis in Hypoxia-Induced Pulmonary Arterial Hypertensive Rats Through Inhibition of the JAK2/STAT3 Signaling Pathway

“…The latest research found that the JAK2/STAT3 pathway participates in the process of AngⅡ-induced myocardial remodeling by promoting myocardial hypertrophy and fibrosis (Ye et al, 2020). In this study, we found that the phosphorylation levels of JAK2 and STAT3 were evidently Magnolol is one of the foremost effective ingredients of traditional Chinese medicine Magnolia Officinalis, which has received widespread attention due to its anti-inflammatory (Zhou et al, 2019) and anti-tumor (Chen et al, 2021a) effects. A recent study reported that magnolol could ameliorate the vascular remodeling in monocrotaline-induced PAH rats (Chang et al, 2018).…”

“…Magnolol is one of the foremost effective ingredients of traditional Chinese medicine Magnolia Officinalis , which has received widespread attention due to its anti-inflammatory ( Zhou et al, 2019 ) and anti-tumor ( Chen et al, 2021a ) effects. A recent study reported that magnolol could ameliorate the vascular remodeling in monocrotaline-induced PAH rats ( Chang et al, 2018 ).…”

The inhibitory effect and mechanism of quetiapine on tumor progression in hepatocellular carcinoma in vivo

“…Inhibition of anti‐apoptotic proteins and induction of apoptosis by complementary agents have been presented to boost the anti‐HCC efficacy of therapeutic agents. 38 , 39 In addition to the reduction of anti‐apoptotic proteins, expression of apoptotic proteins cleaved‐caspase‐3, −8, −9, and Endo‐G was significantly increased by quetiapine treatment (Figure 3 A‐C). Endo‐G is a caspase‐independent death effector to trigger nucleosome DNA fragmentation leading to tumor cell death.…”