MSFTZ, a flavanone derivative, induces human hepatoma cell apoptosis via a reactive oxygen species- and
Meidan Ying1, Chongxing Tu, Huazhou Ying
1Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Abstract:
Hepatocellular carcinoma (HCC) is the most common malignancy of the liver. It is unfortunate that HCCs are highly refractory to conventional chemotherapy, radiation therapy, and even immunotherapy. Thus, novel therapeutic targets need to be sought for the successful treatment of HCCs. We now report that (+/-)-(3aRS,4SR)-2-(2-chloro-4-methylsulfonylphenyl)-4'-chloro-3alpha,4-diethoxy-flavane[4,3-d]-D1,9b-1,2,3-thiadiazoline (MSFTZ), a synthesized flavanone derivative, induced growth arrest and apoptosis of HCCs both in vitro and in vivo. MSFTZ induced a time- and dose-dependent increase in HCC apoptosis through caspase-3 activation and poly(ADP-ribose) polymerase-1 cleavage. Activation of caspase-9 induced by MSFTZ suggested that MSFTZ-induced signaling was mediated through a mitochondrial death pathway. In addition, we observed an elevation of reactive oxygen species (ROS) and a consequent loss of mitochondrial membrane potential, further suggesting that MSFTZ-induced death signaling was mediated through a mitochondrial oxygen stress pathway. These events were associated with a decrease and increase in Bcl-2 and Bax expression, respectively, as well as phosphorylation of mitogen-activated protein kinase (MAPK) and activation of p53-MDM2 pathway. However, the antioxidant N-acetylcysteine opposed MSFTZ-mediated mitochondrial dysfunction, caspase activation, Bcl-2/Bax modulation, and apoptosis, supporting the role of ROS in the apoptotic process. We were surprised that we failed to observe the protective effect of N-acetylcysteine against MSFTZ-induced MAPK activation. Furthermore, MSFTZ had an antitumor effect in vivo by 34.8 to 78.7% reduction of tumor size in SMMC-7721-xenografted nude mice. We conclude that MSFTZ induces HCC cell apoptosis both in vivo and in vitro via caspase- and ROS-dependent mitochondrial pathway. In addition, MSFTZ has potential as a novel therapeutic agent for the treatment of HCC.
Insights
A novel flavanone derivative, MSFTZ, effectively induces apoptosis and growth arrest in hepatocellular carcinoma (HCC) cells. This compound shows significant antitumor effects in vivo, suggesting its potential as a new therapeutic agent for liver cancer.
Area of Science:
- Hepatocellular carcinoma (HCC) research
- Drug discovery and development
- Molecular oncology
Background:
- Hepatocellular carcinoma (HCC) is a prevalent liver cancer with limited treatment options.
- Existing therapies like chemotherapy, radiation, and immunotherapy are often ineffective against HCC.
- Novel therapeutic targets and agents are crucial for improving HCC treatment outcomes.
Purpose of the Study:
- To investigate the therapeutic potential of a synthesized flavanone derivative, MSFTZ, against hepatocellular carcinoma (HCC).
- To elucidate the molecular mechanisms underlying MSFTZ-induced apoptosis and growth arrest in HCC cells.
- To evaluate the in vivo antitumor efficacy of MSFTZ in a preclinical HCC model.
Main Methods:
- In vitro studies using HCC cell lines to assess MSFTZ's effects on apoptosis, cell cycle, and signaling pathways.
- In vivo experiments using SMMC-7721-xenografted nude mice to evaluate MSFTZ's antitumor activity.
- Analysis of key apoptotic markers, including caspase-3, PARP-1 cleavage, mitochondrial membrane potential, ROS production, Bcl-2/Bax expression, and MAPK/p53-MDM2 pathways.
- Assessment of the role of reactive oxygen species (ROS) using the antioxidant N-acetylcysteine.
Main Results:
- MSFTZ induced time- and dose-dependent apoptosis in HCC cells via caspase-3 activation and PARP-1 cleavage.
- MSFTZ triggered apoptosis through the mitochondrial pathway, evidenced by caspase-9 activation, increased ROS, and loss of mitochondrial membrane potential.
- MSFTZ modulated Bcl-2/Bax expression, activated MAPK, and influenced the p53-MDM2 pathway.
- N-acetylcysteine reversed MSFTZ-induced mitochondrial dysfunction, caspase activation, and Bcl-2/Bax changes, confirming the role of ROS.
- MSFTZ demonstrated significant antitumor effects in vivo, reducing tumor size by 34.8% to 78.7%.
Conclusions:
- MSFTZ effectively induces apoptosis in HCC cells both in vitro and in vivo.
- The mechanism involves caspase-dependent and ROS-mediated mitochondrial signaling pathways.
- MSFTZ exhibits promising potential as a novel therapeutic agent for hepatocellular carcinoma treatment.
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