Baicalein Inhibits the Progression and Promotes Radiosensitivity of Esophageal Squamous Cell Carcinoma by Targeting HIF-1A

Abstract

Purpose To explore the mechanism of the effect of baicalein on radioresistance of esophageal cancer, and to provide ideas for the treatment of patients with poor radiotherapy effect of esophageal cancer. Methods The glycolytic rate assay kit was used to detect the changes in glycolytic metabolism in esophageal cancer cells after treatment with baicalein, and mass spectrometry was used to detect whether baicalein could affect the level of glycolysis-related metabolites in esophageal cancer cells. The binding of baicalein to the target protein was simulated by molecular docking technique, the protein expression level was detected by Western Blot, and the changes in the cell cycle were detected by flow cytometry. Results Radiation combined with baicalein could significantly inhibit the proliferation and migration of esophageal cancer cells compared with that of 6 Gy rays alone. The results of the glycolytic rate assay showed that baicalein could inhibit the glycolysis of esophageal cancer cells. Metabonomic studies showed that baicalein could affect the expression levels of glycolysis-related metabolites. The results of network pharmacology showed that baicalein could target several key glycolysis enzymes and glycolysis-related proteins, such as HIF-1A. The results of the WB experiment showed that glycolysis-related proteins and cycle-related proteins were down-regulated after baicalein treatment. Conclusion The main mechanism of baicalein inhibiting radiation resistance of esophageal cancer cells is that targeting HIF-1A protein regulates glucose metabolism and then regulates Cyclin D1/CDK4 axis to change the cell cycle.

Significance of flavonoids targeting PI3K/Akt/HIF-1α signaling pathway in therapy-resistant cancer cells – A potential contribution to the predictive, preventive, and personalized medicine

“…Notably, cells are observed to be most radio-sensitive in G2-M phase and less radio-sensitive in G1 phase. The authors concluded the potential effectiveness of baicalein to enhance radiotherapy efficacy in esophageal cancer [91] .…”

“… Flavonoid Cancer type (resistance) Study details Effects Year Ref. Wogonin CC (cisplatin resistance) HCT116 cells in vitro ↑ sensitivity to cisplatin; ↓ HIF-1α; ↓ glycolysis-related proteins (HK2, PDHK1, LDHA); ↓ glucose uptake and lactate generation; ↓ PI3K/Akt; 2014 [14] Male BALB/c mice (tumor xenograft model – HCT116 transplanted) ↓ growth; ↓ HIF-1α via ↓ PI3K/Akt Baicalein GC (5-FU resistance) AGS cells in vitro ↓ proliferation under hypoxia; ↕ hypoxia-induced 5-FU resistance; ↓ glucose uptake and lactate under hypoxia; ↓ glycolytic-related enzymes under hypoxia (HK2, LDHA, PDK1); ↓ HIF-1α via PTEN/Akt (↓ Akt phosphorylation, ↑ PTEN protein expression) under hypoxia 2015 [30] Baicalein BC (TAM resistance) TAM-resistant BC cell lines (MCF-7TR, T-47DTR, BT-474TR, ZR-75-1TR) ↓ cell growth (OHT + baicalein vs OHT alone); ↓ cell viability, IC 50 (OHT + baicalein); ↓ clonal numbers (baicalein) and further ↓ when OHT + baicalein; ↑ apoptotic effect of OHT; ↓ HIF-1α (↓OHT-induced HIF-1α activation); ↓ aerobic glycolysis; ↕ mitochondrial dysfunction (↑ mitochondrial biogenesis); ↑ OHT-induced mitochondria-mediated ROS (↑ apoptosis) 2021 [8] Female NOD/SCID mice (MCF-7TR cells inoculated) ↑ inhibitory effects of TAM; ↓ tumor proliferation, ↑ apoptosis (TAM + baicalein vs TAM or baicalein alone); ↓ HIF-1α (baicalein or TAM + baicalein); ↑ sensitivity to TAM (↓ aerobic glycolysis and ↑ mitochondrial biosynthesis); ↓ LDHA and ↑ PGC-1α (baicalein or TAM + baicalein) Baicalein EC (radiotherapy resistance) EC cell line KYSE150 cells irradiated with 6 Gy ↓ radiotherapy resistance (↓ proliferation and not forming clones in baicalein + radiation vs radiation alone group); ↓ glycolysis (↓HIF-1α and HIF-1α PKM2); ↓ G1-related genes and proteins (regulation of CyclinD1/CDK4) 2022 [91] Oroxylin A Glioma Hypoxic model of glioma cells (human U251, rat C6, mouse GL261) in vitro ↑ sensitivity of TMZ; …”

Hypoxia inducible factor 1-alpha in the pathogenesis of abdominal aortic aneurysms in vivo: A narrative review

“… 33 , 34 HIF-1α inhibitors aim to disrupt the HIF-1α pathway, thus, potentially inhibiting the adaptation of cancer cells to hypoxia and impeding their survival and proliferation. 35 , 36 …”

Integrated bioinformatics and network pharmacology to identify the therapeutic target and molecular mechanisms of Scutellaria barbata plus Hedyotis diffusa herb pair on esophageal squamous cell carcinoma

“…Zhao et al [48] found that quercetin inhibited the formation of esophageal precancerous lesions, and the inhibition was associated with decreased in ammation and esophageal cancer cell proliferation. Baicalein, a natural avonoid, not only could directly induce apoptosis, but also inhibits the progression and promotes radiosensitivity for ESCC [49,50] . Luteolin is also plant avonoid which can inhibits cell proliferation and induces cell apoptosis for human ESCC [51,52] .…”