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In Vivo Effects of Bay 11-7082 on Fibroid Growth and Gene Expression: A Preclinical Study
Tsai-Der Chuang1, Nhu Ton1, Shawn Rysling1
1The Lundquist Institute for Biomedical Innovation, Torrance, CA 90502, USA.
Abstract:
Current medical therapies for fibroids have major limitations due to their hypoestrogenic side effects. Based on our previous work showing the activation of NF-kB in fibroids, we hypothesized that inhibiting NF-kB in vivo would result in the shrinkage of tumors and reduced inflammation. Fibroid xenografts were implanted in SCID mice and treated daily with Bay 11-7082 (Bay) or vehicle for two months. Bay treatment led to a 50% reduction in tumor weight. RNAseq revealed decreased expression of genes related to cell proliferation, inflammation, extracellular matrix (ECM) composition, and growth factor expression. Validation through qRT-PCR, Western blotting, ELISA, and immunohistochemistry (IHC) confirmed these findings. Bay treatment reduced mRNA expression of cell cycle regulators (CCND1, E2F1, and CKS2), inflammatory markers (SPARC, TDO2, MYD88, TLR3, TLR6, IL6, TNFα, TNFRSF11A, and IL1β), ECM remodelers (COL3A1, FN1, LOX, and TGFβ3), growth factors (PRL, PDGFA, and VEGFC), progesterone receptor, and miR-29c and miR-200c. Collagen levels were reduced in Bay-treated xenografts. Western blotting and IHC showed decreased protein abundance in certain ECM components and inflammatory markers, but not cleaved caspase three. Ki67, CCND1, and E2F1 expression decreased with Bay treatment. This preclinical study suggests NF-kB inhibition as an effective fibroid treatment, suppressing genes involved in proliferation, inflammation, and ECM remodeling.
Insights
NF-kB inhibition effectively reduced uterine fibroid tumors in mice by decreasing genes involved in cell growth and inflammation. This approach offers a promising alternative to current therapies with significant hypoestrogenic side effects.
Area of Science:
- Reproductive biology
- Oncology
- Molecular medicine
Background:
- Current uterine fibroid treatments have significant hypoestrogenic side effects.
- Previous research indicated Nuclear Factor-kappa B (NF-kB) activation in fibroids.
Purpose of the Study:
- To investigate the efficacy of inhibiting NF-kB in vivo for treating uterine fibroids.
- To assess the impact of NF-kB inhibition on fibroid tumor shrinkage and inflammation.
Main Methods:
- Uterine fibroid xenografts were established in SCID mice.
- Mice were treated daily with Bay 11-7082 (Bay) or a vehicle control for two months.
- Tumor weight, gene expression (RNAseq, qRT-PCR), protein levels (Western blotting, ELISA, IHC), and collagen content were analyzed.
Main Results:
- Bay treatment resulted in a 50% reduction in tumor weight.
- NF-kB inhibition decreased the expression of genes related to cell proliferation, inflammation, extracellular matrix (ECM) remodeling, and growth factors.
- Key markers of proliferation (Ki67, CCND1, E2F1) and inflammation were significantly reduced.
Conclusions:
- NF-kB inhibition is a potential therapeutic strategy for uterine fibroids.
- This approach effectively suppresses fibroid growth by targeting pathways involved in proliferation, inflammation, and ECM remodeling.
- Further preclinical studies are warranted to explore this therapeutic avenue.
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