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

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.

• Authors: Mingxin Zuo, Chenglong Li, Jiayuh Lin, Milind Javle
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 13 Pg. 10940-9 (May 10 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25883212 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Anthraquinones
• LLL12 compound
• RNA, Messenger
• STAT3 Transcription Factor
• Sulfonamides

Topics

• Animals
• Anthraquinones (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Carcinoma, Hepatocellular (drug therapy, metabolism, pathology)
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Female
• Flow Cytometry
• Fluorescent Antibody Technique
• Humans
• Liver Neoplasms (drug therapy, metabolism, pathology)
• Mice
• Mice, Nude
• Phosphorylation (drug effects)
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• STAT3 Transcription Factor (antagonists & inhibitors, genetics, metabolism)
• Sulfonamides (pharmacology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays