MSFTZ, a flavanone derivative, induces human hepatoma cell apoptosis via a reactive oxygen species- and caspase-dependent mitochondrial pathway.
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.
Ying
Meidan
M
Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Tu
Chongxing
C
Ying
Huazhou
H
Hu
Yongzhou
Y
He
Qiaojun
Q
Yang
Bo
B
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D001578:Benzopyrans / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D044950:Flavanones; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009368:Neoplasm Transplantation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013830:Thiadiazoles / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C516246:2-(2-chloro-4-methylsulfonylphenyl)-4'-chloro-3a,4-diethoxyflavane(4,3-d)-delta(1,9b)-1,2,3-thiadiazoline; D000970:Antineoplastic Agents; D000975:Antioxidants; D001578:Benzopyrans; D044950:Flavanones; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D013830:Thiadiazoles; D016159:Tumor Suppressor Protein p53; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases; D000111:Acetylcysteine