Elsevier

Neoplasia

Volume 12, Issue 1, January 2010, Pages 39-50, IN5
Neoplasia

A Novel Small Molecule, LLL12, Inhibits STAT3 Phosphorylation and Activities and Exhibits Potent Growth-Suppressive Activity in Human Cancer Cells1,2

https://doi.org/10.1593/neo.91196Get rights and content
Under a Creative Commons license
open access

Constitutive activation of signal transducer and activator of transcription 3 (STAT3) signaling is frequently detected in cancer, promoting its emergence as a promising target for cancer treatment. Inhibiting constitutive STAT3 signaling represents a potential therapeutic approach. We used structure-based design to develop a nonpeptide, cell-permeable, small molecule, termed as LLL12, which targets STAT3. LLL12 was found to inhibit STAT3 phosphorylation (tyrosine 705) and induce apoptosis as indicated by the increases of cleaved caspase-3 and poly (ADP-ribose) polymerase in various breast, pancreatic, and glioblastoma cancer cell lines expressing elevated levels of STAT3 phosphorylation. LLL12 could also inhibit STAT3 phosphorylation induced by interleukin-6 in MDA-MB-453 breast cancer cells. The inhibition of STAT3 by LLL12 was confirmed by the inhibition of STAT3 DNA binding activity and STAT3-dependent transcriptional luciferase activity. Downstream targets of STAT3, cyclin D1, Bcl-2, and survivin were also downregulated by LLL12 at both protein and messenger RNA levels. LLL12 is a potent inhibitor of cell viability, with half-maximal inhibitory concentrations values ranging between 0.16 and 3.09 µM, which are lower than the reported JAK2 inhibitor WP1066 and STAT3 inhibitor S3I-201 in six cancer cell lines expressing elevated levels of STAT3 phosphorylation. In addition, LLL12 inhibits colony formation and cell migration and works synergistically with doxorubicin and gemcitabine. Furthermore, LLL12 demonstrated a potent inhibitory activity on breast and glioblastoma tumor growth in a mouse xenograft model. Our results indicate that LLL12 may be a potential therapeutic agent for human cancer cells expressing constitutive STAT3 signaling.

Abbreviations

DMEM
Dulbecco's modified Eagle medium
DMSO
dimethyl sulfoxide
PARP
poly (ADP-ribose) polymerase
STAT
signal transducer and activator of transcription
Tyr705
tyrosine 705

Cited by (0)

1

This research was partly funded by The Susan G. Komen Breast Cancer Foundation, The James S. McDonnell Foundation, The National Foundation for Cancer Research, and NIHR21 grant (R21CA133652-01) to Jiayuh Lin.

2

This article refers to supplementary materials, which are designated by Table W1 and Figure W1 and are available online at www.neoplasia.com.