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MSFTZ, a flavanone derivative, induces human hepatoma cell apoptosis via a reactive oxygen species- and caspase-dependent mitochondrial pathway.
J Pharmacol Exp Ther. 2008 Jun; 325(3):758-65.JP

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.

Authors+Show Affiliations

Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18323457

Citation

Ying, Meidan, et al. "MSFTZ, a Flavanone Derivative, Induces Human Hepatoma Cell Apoptosis Via a Reactive Oxygen Species- and Caspase-dependent Mitochondrial Pathway." The Journal of Pharmacology and Experimental Therapeutics, vol. 325, no. 3, 2008, pp. 758-65.
Ying M, Tu C, Ying H, et al. MSFTZ, a flavanone derivative, induces human hepatoma cell apoptosis via a reactive oxygen species- and caspase-dependent mitochondrial pathway. J Pharmacol Exp Ther. 2008;325(3):758-65.
Ying, M., Tu, C., Ying, H., Hu, Y., He, Q., & Yang, B. (2008). MSFTZ, a flavanone derivative, induces human hepatoma cell apoptosis via a reactive oxygen species- and caspase-dependent mitochondrial pathway. The Journal of Pharmacology and Experimental Therapeutics, 325(3), 758-65. https://doi.org/10.1124/jpet.107.135657
Ying M, et al. MSFTZ, a Flavanone Derivative, Induces Human Hepatoma Cell Apoptosis Via a Reactive Oxygen Species- and Caspase-dependent Mitochondrial Pathway. J Pharmacol Exp Ther. 2008;325(3):758-65. PubMed PMID: 18323457.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - MSFTZ, a flavanone derivative, induces human hepatoma cell apoptosis via a reactive oxygen species- and caspase-dependent mitochondrial pathway. AU - Ying,Meidan, AU - Tu,Chongxing, AU - Ying,Huazhou, AU - Hu,Yongzhou, AU - He,Qiaojun, AU - Yang,Bo, Y1 - 2008/03/06/ PY - 2008/3/8/pubmed PY - 2008/6/17/medline PY - 2008/3/8/entrez SP - 758 EP - 65 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 325 IS - 3 N2 - 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. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/18323457/MSFTZ_a_flavanone_derivative_induces_human_hepatoma_cell_apoptosis_via_a_reactive_oxygen_species__and_caspase_dependent_mitochondrial_pathway_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=18323457 DB - PRIME DP - Unbound Medicine ER -