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

Kwang Hwa Jung, Wonbeak Yoo, Heather Stevenson-Lerner, 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

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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

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Hepatocellular Carcinoma
Therapeutics
Aspartate Aminotransferases
Liver
Neoplasms
Toll-Like Receptor 1
Non-alcoholic Fatty Liver Disease
Drug Design
Fatty Liver
Liver Neoplasms
Growth
Alanine Transaminase
Bile
Liver Cirrhosis
Hepatocytes
Fibrosis
Research Design
Neoplasm Metastasis
Inflammation
Gene Expression

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Multifunctional effects of a small-molecule STAT3 inhibitor on NASH and hepatocellular carcinoma in mice. / Jung, Kwang Hwa; Yoo, Wonbeak; Stevenson-Lerner, Heather; Deshpande, Dipti; Shen, Hong; Gagea, Mihai; Yoo, Suk Young; Wang, Jing; Eckols, T. Kris; Bharadwaj, Uddalak; Tweardy, David J.; Beretta, Laura.

In: Clinical Cancer Research, Vol. 23, No. 18, 15.09.2017, p. 5537-5546.

Research output: Contribution to journalArticle

Jung, KH, Yoo, W, Stevenson-Lerner, H, Deshpande, D, Shen, H, Gagea, M, Yoo, SY, Wang, J, Eckols, TK, Bharadwaj, U, Tweardy, DJ & Beretta, L 2017, 'Multifunctional effects of a small-molecule STAT3 inhibitor on NASH and hepatocellular carcinoma in mice', Clinical Cancer Research, vol. 23, no. 18, pp. 5537-5546. https://doi.org/10.1158/1078-0432.CCR-16-2253
Jung, Kwang Hwa ; Yoo, Wonbeak ; Stevenson-Lerner, Heather ; Deshpande, Dipti ; Shen, Hong ; Gagea, Mihai ; Yoo, Suk Young ; Wang, Jing ; Eckols, T. Kris ; Bharadwaj, Uddalak ; Tweardy, David J. ; Beretta, Laura. / Multifunctional effects of a small-molecule STAT3 inhibitor on NASH and hepatocellular carcinoma in mice. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 18. pp. 5537-5546.
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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.",
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AU - Jung, Kwang Hwa

AU - Yoo, Wonbeak

AU - Stevenson-Lerner, Heather

AU - Deshpande, Dipti

AU - Shen, Hong

AU - Gagea, Mihai

AU - Yoo, Suk Young

AU - Wang, Jing

AU - Eckols, T. Kris

AU - Bharadwaj, Uddalak

AU - Tweardy, David J.

AU - Beretta, Laura

PY - 2017/9/15

Y1 - 2017/9/15

N2 - 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.

AB - 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.

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