Multi-functional effects of a small-molecule STAT3 inhibitor on NASH and HCC in mice

Purpose: The incidence of hepatocellular carcinoma (HCC) is increasing in the United States and liver cancer is the second leading cause of cancer-related mortality worldwide. Non-alcoholic steatohepatitis (NASH) is becoming an important risk for HCC and most patients with HCC have underlying liver cirrhosis and compromised liver function, which limit treatment options. Thus, novel therapeutic strategies to prevent or treat HCC in the context of NASH and cirrhosis are urgently needed. <br /><br />Experimental Design: Constitutive activation of signal transducer and activator of transcription 3 (STAT3) is frequently detected in HCC tumors. STAT3 signaling plays a pivotal role in HCC survival, growth, angiogenesis and metastasis. We identified C188-9, a novel small-molecule STAT3 inhibitor using computer-aided rational drug design. In this study, we evaluated the therapeutic potential of C188-9 for HCC treatment and prevention. <br /><br />Results: C188-9 showed antitumor activity in vitro in three HCC cell lines. In mice with hepatocyte-specific deletion of Pten (HepPten- mice), C188-9 treatment blocked HCC tumor growth, reduced tumor development, and reduced liver steatosis, inflammation and bile ductular reactions, resulting in improvement of the pathological lesions of NASH. Remarkably, C188-9 also greatly reduced liver injury in these mice as measured by serum AST and ALT levels. Analysis of gene expression showed that C188-9 treatment of HepPten- mice resulted in inhibition of signaling pathways downstream of STAT3, STAT1, TREM-1, and Toll-like receptors. In contrast, C188-9 treatment increased liver specification and differentiation gene pathways. <br /><br />Conclusions: Our results suggest that C188-9 should be evaluated further for the treatment and/or prevention of HCC.

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