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Cited by 124Cytokine Signaling Pathways and InteractionsHepatocellular Carcinoma Treatment and PrognosisLiver physiology and pathology

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

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Jung, Kwang Hwa, Yoo, Wonbeak, Stevenson, Heather L., Deshpande, Dipti, Shen, Hong, Gagea, Mihai, Yoo, Suk-Young, Wang, Jing +4 more·2017·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-16-2253PMC PMC5873583

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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. Clin Cancer Res; 23(18); 5537–46. ©2017 AACR.

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  • TTI-101 administration to hepatocyte-specific Pten KO mice, a model of NASH progressing to cirrhosis, reduced liver injury and fibrosis.

    “We demonstrated that TTI-101 administration to hepatocyte-specific Pten KO (HepPten-) mice, a model of nonalcoholic steatohepatitis (NASH) progressing to cirrhosis, reduced liver injury and fibrosis”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Jung et al., 2017

    The Results section, “C188-9 Treatment Improves NASH and Liver Function” (page unavailable), reports reduced fibrosis and lower ALT and AST levels in hepatocyte-specific Pten knockout mice. The paper calls the administered compound C188-9, not TTI-101, and describes the mice as developing NASH before HCC; our copy does not establish that this model progresses to cirrhosis or identify the two drug names as equivalent. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • TTI-101 demonstrated potent antitumor activity in several preclinical cancer models, including NSCLC, head and neck squamous cell carcinoma, hepatocellular carcinoma, and ER-positive breast cancer resistant to inhibitors of cyclin-dependent kinases.

    “TTI-101 demonstrated potent antitumor activity in several preclinical cancer models, including NSCLC (Lewis et al., 2015), head and neck squamous cell carcinoma (Bharadwaj et al., 2016a), hepatocellular carcinoma (Jung et al., 2017), and ER-positive breast cancer resistant to inhibitors of cyclin-dependent kinases (Kettner et al., 2019).”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Jung et al., 2017

    The Results section ('C188-9 Treatment Resulted in Tumor Growth Arrest'; page unavailable) reports significantly slower tumor growth in the HCC mouse model. This supports the HCC portion of the citing sentence, but our copy calls the compound C188-9 and does not establish that it is TTI-101. The other cancer models have separate citations in the citing sentence and are not attributed to this paper. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
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.
Affiliations
  • The University of Texas MD Anderson Cancer Center (US)
  • The University of Texas Medical Branch at Galveston (US)
Corresponding author
Beretta, Laura
ORCID
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2017-05-22
Volume
23
Issue
18
Pages
5537-5546
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
DOI
10.1158/1078-0432.ccr-16-2253
PMC
PMC5873583
OpenAlex
W2618875352
Cited by
124
References
3
Citations by year
2026: 7 · 2025: 11 · 2024: 18 · 2023: 13 · 2022: 26 · 2021: 13 · 2020: 10 · 2019: 18 · 2018: 6 · 2017: 2
FWCI
4.34
Type
journal article
Language
en
Open access
Locations
  • Clinical Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • NIH (P30CA016672)
  • University of Texas MD Anderson Cancer Center (CA016672)
  • Cancer Prevention and Research Institute of Texas (DP150069)
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
STAT3 inhibitor, hepatocellular carcinoma, nonalcoholic steatohepatitis, liver cirrhosis, PTEN, hepatic steatosis, liver inflammation, STAT1, TREM-1, Toll-like receptors, hepatocyte-specific deletion, anticancer activity, liver injury
MeSH terms
Benzenesulfonamides, Animals, Antineoplastic Agents, Biopsy, Cell Survival, Disease Models, Animal, Carcinoma, Hepatocellular, Humans, Immunohistochemistry, Liver Function Tests, Liver Neoplasms, Magnetic Resonance Imaging, Naphthols, Sulfonamides, Signal Transduction, Cytokines, Mice, Knockout, Inflammation Mediators, Gene Expression Profiling, Xenograft Model Antitumor Assays, Cell Line, Tumor, Cell Proliferation, STAT3 Transcription Factor, PTEN Phosphohydrolase, Mice, Non-alcoholic Fatty Liver Disease

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