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

Mingxin Zuo,Chenglong Li,Milind Javle,Jiayuh Lin

doi:10.18632/oncotarget.3458

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.

Highlights

Liver cancer is the sixth most common malignancy and the third-leading cause of cancer death worldwide
To examine the cytotoxic activity of LLL12, the human Hepatocellular carcinoma (HCC) cell lines SNU387, SNU398, SNU449, and Hep3B were treated with LLL12 at serial concentrations and assessed by the 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay
Morphologic assays of SNU387, SNU398, SNU449, and Hep3B treated with LLL12 at 5 μM or 10 μM for 24 h showed that LLL12 inhibited cell growth and induced substantial apoptosis in most of the cell lines at 10 μM (Figure 2)

Summary

Introduction

Liver cancer is the sixth most common malignancy and the third-leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) accounts for 90% of all liver cancers. In the United States, the estimated new liver cancer cases and deaths in 2014 account for 33,190 and 23,000, respectively [1]. There is no effective therapy for HCC, Surgical excision by partial or total hepatectomy represents the only potentially curative therapy for HCC, but many patients would be in an advanced stage of disease at initial diagnosis. Most of these patients aren’t candidates for surgery. There is a pressing need for the development of new approaches in HCC therapy

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