Abstract
Baicalein is one of the bioactive compounds extracted from Scutellaria baicalensis. Recent studies indicated the antitumor effects of baicalein, however, the underlying mechanisms are needed to be further determined. In this study, we found that baicalein could inhibit the tumor growth in mice models of breast cancer and melanoma and worked as an immunomodulator to promote the infiltration of tumor-associated macrophages (TAMs) and skew the TAMs towards the M1-like phenotype. Baicalein also induced M1-like phenotype polarization in THP-1-derived macrophages. Meanwhile, the expression of pro-inflammatory factors associated with M1 macrophages, including TNF-α, IL-1β, CXCL9 and CXCL10, were increased after baicalein treatment. Mechanistically, the RNA-seq data suggested that baicalein potentiated the M1 macrophage polarization via the NF-κB/TNF-α signaling pathway. ELISA and confocal microscopy assay confirmed that baicalein significantly induced the production of TNF-α and the activation of NF-κB, while TNF-α neutralization inhibited baicalein-induced macrophage polarization toward M1, and NF-κB P65 knock-down suppressed baicalein-induced TNF-α production in THP-1-derived macrophages. Phosphoinositide 3-kinase (PI3k) γ has been reported as a key molecule in macrophage polarization, and inhibition of PI3Kγ activates the NF-κB-related inflammatory signals. Our pharmacological network analysis predicted that PI3Kγ might be one of the major targets of baicalein. The results from the docking program and surface plasmon resonance (SPR) confirmed that baicalein displayed good binding activity to PI3Kγ. We further found that baicalein not only exhibited a direct inhibitory effect on the protein kinase activity of PI3Kγ, but also reduced the mRNA and protein expression of PI3Kγ, indicating that baicalein might be a novel PI3Kγ inhibitor. In summary, baicalein mediated the TAMs skewing to M1-TAMs, and then retarded tumor growth. These effects, at least in part, were linked to the PI3Kγ/NF-κB signaling.
Highlights
Cancer, one of the leading causes of death globally, has always been a serious threat to public health and a formidable challenge for the current health care system
A laser-scanning confocal microscope was used to detect the nuclear transfer of NF-κB P65 and we found that baicalein treatment could markedly increase P65 nuclear translocation in M1 macrophages (Figure 3E)
The application of baicalein, as a main bioactive ingredient extracted from the root of medical herb Scutellaria baicalensis, has been studied in the treatment of a variety of cancers, such as breast cancer, NSCLC, nasopharyngeal carcinoma, hepatocellular carcinoma, and the underlying mechanisms mainly focus on inducing apoptosis and autophagy, cell cycle arrest, inhibiting proliferation and invasion of tumor cells (Bie et al, 2017; Yan et al, 2018; Guo et al, 2019; Nik Salleh et al, 2020; Zhang et al, 2020)
Summary
One of the leading causes of death globally, has always been a serious threat to public health and a formidable challenge for the current health care system. Solid tumors, such as breast cancer and melanoma, can be treated with conventional therapeutic options including surgical resection, radiotherapy, chemotherapy, as well as increasing numbers of treatment strategies developed in Baicalein Potentiated M1 Polarization the past decades. The M1 phenotype typically produces tumor necrosis factor (TNF), interleukin (IL)-12 and interferon-γ (IFN-γ) inducible chemokines C-X-C motif chemokine ligand (CXCL) 9 and CXCL10 to exert proinflammatory and antitumor effects, whereas M2 macrophages, mainly identified by the production of IL-10 and Arg-1, are known to inhibit inflammatory responses and promote tumor progression (Mantovani et al, 2002; Murray et al, 2014; Lee et al, 2019). Reeducating the TAMs to the M1 phenotype might be a promising strategy for cancer treatment (Li et al, 2019)
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