Luteolin combined with low‐dose paclitaxel synergistically inhibits epithelial–mesenchymal transition and induces cell apoptosis on esophageal carcinoma in vitro and in vivo

Abstract

Although paclitaxel is a promising frontline chemotherapy agent for various malignancies, the clinical applications have been restricted by side effects, drug resistance, and cancer metastasis. The combination of paclitaxel and other agents could be the promising strategies against malignant tumor, which enhances the antitumor effect through synergistic effects, reduces required drug concentrations, and also suppresses tumorigenesis in multiple ways. In this study, we found that luteolin, a natural flavonoid compound, combined with low-dose paclitaxel synergistically regulated the proliferation, migration, epithelial-mesenchymal transition (EMT), and apoptosis of esophageal cancer cells in vitro, as well as synergistically inhibited tumor growth without obvious toxicity in vivo. The molecular mechanism of inhibiting cell migration and EMT processes may be related to the inhibition of SIRT1, and the mechanism of apoptosis induction is associated with the reactive oxygen species (ROS)/c-Jun N-terminal kinase (JNK) pathway-mediated activation of mitochondrial apoptotic pathway.

A Network Pharmacological Elucidation of the Systematic Treatment Activities and Mechanisms of the Herbal Drug FDY003 Against Esophageal Cancer

“…87 Luteolin suppresses cell cycle progression, growth, survival, EMT, migration, and chemoresistance by the modulation of cyclin, survivin, Myc, p21, p53, poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP), Bim, caspase, SIRT1, c-Jun N-terminal kinase (JNK), and ROS signaling. 88 Quercetin targets cyclin, DNA methyltransferase 1, histone deacetylase 1, caspase, p16, NF-kappa B, growth arrest and DNA damage-inducible protein (GADD)-β, p53-inducible gene 3, p18, E-cadherin, VEGF-A, matrix metalloproteinase (MMP), miR-1-3p/ transgelin-2, and phosphatase and tensin homolog (PTEN) pathways 89 ; these effects result in the suppression of drug resistance, growth, proliferation, invasion, angiogenesis, and cancer stemness of EC cells. 89 The anticancer properties of FDY003 against diverse kinds of cancer cells have been previously investigated.…”

Epigenetic modifications in esophageal cancer: An evolving biomarker

“…Studies have shown that resveratrol, a powerful alternative to antioxidants, inhibits a variety of cancers ( Rauf et al, 2018 ). Luteolin inhibits paclitaxel resistance in esophageal cancer and synergistically inhibits the EMT process in combination with low-dose paclitaxel, thereby inducing apoptosis in esophageal cancer in vitro and in vivo ( Zhao Y et al, 2021 ; Qin et al, 2021 ). In addition, apigenin, icaritin, oridonin, berberine and curcumin have all been shown to have anti-esophageal cancer efficacy ( Jiang et al, 2017 ; Han et al, 2018 ; Jiang et al, 2019 ; Kwiecien et al, 2019 ; Qiu et al, 2019 ).…”

Synergistic effects of flavonoids and paclitaxel in cancer treatment: a systematic review

“…The tumorigenicity of paclitacel-resistant oesophageal cancer cells was also inhibited by luteolin and this effect was achieved without significant in vivo damage [ 107 ]. Furthermore, as Qin et al study, luteolin could have substantial potency in clinical application and was presented as a new chemosensitizer agent in the treatment of esophageal cancer [ 108 ]. Using a low dose of paclitaxel with luteolin was shown to have synergistic effects on the regulation of esophageal cancer cell migration, proliferation, EMT, and apoptosis [ 108 ].…”