Multifunctional effects of a small-molecule STAT3 inhibitor on NASH and hepatocellular carcinoma in mice

Kwang Hwa Jung, Wonbeak Yoo, Heather L. Stevenson, Dipti Deshpande, Hong Shen, Mihai Gagea, Suk Young Yoo, Jing Wang, T. Kris Eckols, Uddalak Bharadwaj, David J. Tweardy, Laura Beretta

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Purpose: The incidence of hepatocellular carcinoma is increasing in the United States, and liver cancer is the second leading cause of cancer-related mortality worldwide. Nonalcoholic steatohepatitis (NASH) is becoming an important risk for hepatocellular carcinoma, and most patients with hepatocellular carcinoma have underlying liver cirrhosis and compromised liver function, which limit treatment options. Thus, novel therapeutic strategies to prevent or treat hepatocellular carcinoma in the context of NASH and cirrhosis are urgently needed. Experimental Design: Constitutive activation of STAT3 is frequently detected in hepatocellular carcinoma tumors. STAT3 signaling plays a pivotal role in hepatocellular carcinoma 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 hepatocellular carcinoma treatment and prevention. Results: C188-9 showed antitumor activity in vitro in three hepatocellular carcinoma cell lines. In mice with hepatocyte-specific deletion of Pten (HepPten mice), C188-9 treatment blocked hepatocellular carcinoma 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 aspartate aminotransferase and alanine transaminase 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. Conclusions: Our results suggest that C188-9 should be evaluated further for the treatment and/or prevention of hepatocellular carcinoma.

Original languageEnglish (US)
Pages (from-to)5537-5546
Number of pages10
JournalClinical Cancer Research
Volume23
Issue number18
DOIs
StatePublished - Sep 15 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Jung, K. H., Yoo, W., Stevenson, H. L., Deshpande, D., Shen, H., Gagea, M., Yoo, S. Y., Wang, J., Eckols, T. K., Bharadwaj, U., Tweardy, D. J., & Beretta, L. (2017). Multifunctional effects of a small-molecule STAT3 inhibitor on NASH and hepatocellular carcinoma in mice. Clinical Cancer Research, 23(18), 5537-5546. https://doi.org/10.1158/1078-0432.CCR-16-2253