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LLL12B, a Novel Small-Molecule STAT3 Inhibitor, Induces Apoptosis and Suppresses Cell Migration and Tumor Growth in
Li Pan1, Xiang Chen1, Feyruz Virgilia Rassool2
1Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA.
Abstract:
Persistent STAT3 signaling plays a pivotal role in human tumor malignancy, including triple-negative breast cancer (TNBC). There are few treatment options currently available for TNBC; thus, given its importance to cancer, STAT3 is a potential cancer therapeutic target and is the focus of drug discovery efforts. In this study, we tested a novel orally bioavailable small-molecule STAT3 inhibitor, LLL12B, in human MDA-MB-231, SUM159, and murine 4T1 TNBC cell lines. TNBC cells frequently expressed persistent STAT3 phosphorylation and their cell viability was sensitive to STAT3 knockdown by siRNA. LLL12B selectively inhibited the IL-6-mediated induction of STAT3 phosphorylation, but had little effect on the IFN-γ-mediated induction of STAT1 phosphorylation nor the EGF-mediated induction of ERK phosphorylation. In addition, targeting STAT3 with LLL12B induced apoptosis, reduced colony formation ability, and inhibited cell migration in TNBC cells. Furthermore, LLL12B suppressed the tumor growth of the MDA-MB-231 TNBC cells in a mammary fat pad mouse tumor model in vivo. Together, our findings support the concept that targeting persistent STAT3 signaling using the novel small-molecule LLL12B is a potential approach for TNBC therapy.
Insights
A new drug, LLL12B, effectively targets persistent STAT3 signaling in triple-negative breast cancer (TNBC) cells. This small molecule inhibits tumor growth and offers a promising new therapeutic strategy for TNBC patients.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Persistent STAT3 signaling is crucial in triple-negative breast cancer (TNBC) malignancy.
- Limited treatment options exist for TNBC, highlighting STAT3 as a key therapeutic target.
Purpose of the Study:
- To evaluate the efficacy of a novel small-molecule STAT3 inhibitor, LLL12B, in preclinical TNBC models.
- To investigate LLL12B's effects on TNBC cell viability, apoptosis, colony formation, and migration.
Main Methods:
- Testing LLL12B in human (MDA-MB-231, SUM159) and murine (4T1) TNBC cell lines.
- Assessing LLL12B's selective inhibition of STAT3 phosphorylation.
- Evaluating LLL12B's impact on TNBC cell proliferation and migration in vitro and tumor growth in vivo.
Main Results:
- LLL12B selectively inhibited IL-6-induced STAT3 phosphorylation without affecting STAT1 or ERK pathways.
- Targeting STAT3 with LLL12B induced apoptosis, reduced colony formation, and inhibited migration in TNBC cells.
- LLL12B suppressed MDA-MB-231 TNBC tumor growth in a mouse model.
Conclusions:
- Persistent STAT3 signaling is a viable target for TNBC therapy.
- The novel small-molecule inhibitor LLL12B demonstrates significant preclinical efficacy against TNBC.
- LLL12B represents a potential therapeutic approach for treating triple-negative breast cancer.
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