MSFTZ, a Flavanone Derivative, Induces Human Hepatoma Cell Apoptosis via a Reactive Oxygen Species- and Caspase-Dependent Mitochondrial Pathway

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 (Ϯ)-(3aRS,4SR)-2-(2-chloro-4-methylsulfonylphenyl)-4Ј-chloro-3␣,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.Hepatocellular carcinoma (HCC) is currently the fifth most common solid tumor worldwide and the fourth leading cause of cancer-related death, and its incidence is rising in many countries (El-Serag, 2004;Thomas and Zhu, 2005). It is usually treated by surgical resection or liver transplantation, with curative options for the patients when the disease is diagnosed at an early stage. However, approximately 70% of patients are inoperable because of advanced tumor growth or liver cirrhosis, or, alternatively, the hepatoma belongs to the group of cancers that are resistant to systemic chemotherapies, radiation therapy, and even immunotherapy (Wirth et al., 2005). Thus, novel therapeutic strategies are needed to improve the efficacy in treating HCC.Natural products derived from plants have recently received much attention as potential chemopreventive and chemotherapeutic agents. Flavanones (Fig. 1A), a subclass of flavonoids, are plant polyphenols found in vegetables, fruit, and beverages of plant origin that is well known for their physiological antipyretic, analgesic, and anti-inflammatory activities. The antitumor ...

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