Received for publication December 27, 2007.
Revised March 3, 2008.
Accepted for publication March 4, 2008.

MSFTZ, a flavanone derivative, induces human hepatoma cells apoptosis via a reactive oxygen species and caspase-dependent mitochondrial pathway

Abstract

Hepatocellular carcinoma (HCC) is the most common malignancy of the liver. Unfortunately, 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-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 HCCs apoptosis through caspase-3 activation and PARP-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 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 MAPK and activation of p53-MDM2 pathway. The antioxidant N-acetylcysteine, however, 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 NAC against MSFTZ-induced MAPK activation. Furthermore, MSFTZ had an anti-tumor effect in vivo by 34.8-78.7% reduction of tumor size in SMMC-7721-xenografted nude mice. We conclude that MSFTZ induces HCC cells 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.

Key words: Hepatocellular carcinoma, apoptosis, caspase, flavanone derivative, mitochondrial pathway, reactive oxygen species