Oncotarget

Research Papers:

LLL12, a novel small inhibitor targeting STAT3 for hepatocellular carcinoma therapy

Mingxin Zuo _, Chenglong Li, Jiayuh Lin and Milind Javle

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Oncotarget. 2015; 6:10940-10949. https://doi.org/10.18632/oncotarget.3458

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Abstract

Mingxin Zuo1, Chenglong Li2, Jiayuh Lin3, Milind Javle1

1Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

2Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA

3Center for Childhood Cancer, The Research Institute at Nationwide Children’s Hospital, Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio 43205, USA

Correspondence to:

Mingxin Zuo, e-mail: [email protected]

Keywords: STAT3, hepatocellular carcinoma, LLL12, small molecular inhibitor

Received: February 13, 2015     Accepted: February 24, 2015     Published: March 26, 2015

ABSTRACT

The constitutive activation of signal transducer and activator of transcription 3 (STAT3) is frequently detected in clinical incidences of hepatocellular carcinoma (HCC) but not in normal human hepatocytes. STAT3 signaling plays pivotal roles in angiogenesis, survival, metastasis, and growth of HCC. Recent evidence suggests that the blockade of aberrant STAT3 pathways can be exploited as a therapeutic strategy for HCC. We have developed the novel small molecular STAT3 inhibitor LLL12 on the basis of curcumin structure using computer-aided rational design. LLL12 has shown antitumor activity in various solid tumors including breast, brain, pancreatic cancer, and glioblastoma in vitro and in vivo. In this study, we hypothesized LLL12 inhibits STAT3 phosphorylation at tyrosine 705 (Y705) in HCC and show antitumor activity in HCC in vitro and in vivo. Our results show that LLL12 selectively inhibited HCC cell proliferation and induced apoptosis in SNU387, SNU398, SNU449, and Hep3B HCC cells in vitro. Furthermore, LLL12 at 5 mg/kg/day significantly inhibited the growth of SNU398 xenografts in nude mice. Collectively, our results indicate that LLL12 could be used to target STAT3 for the effective prevention or treatment of HCC.


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