Hesperetin Promotes Cisplatin−Induced Apoptosis of Gastric Cancer In Vitro and In Vivo by Upregulating PTEN Expression

Abstract

As one of the most common malignant gastrointestinal tumors, gastric cancer (GC) has a high incidence and poor prognosis. Cisplatin (DDP) is often used as chemotherapy for advanced GC; however, the high incidence of drug resistance remains a problem. The use of several anti-tumor drugs as combined chemotherapy is an effective strategy. Hesperetin has anti-tumor ability via its pro-apoptotic effect on various human cancers, both in vitro and in vivo , with no significant toxicity. However, a combination of DDP and hesperetin in GC has not been reported. The present study aimed to investigate the in vitro and in vivo chemosensitization effect and mechanism of hesperetin-augmented DDP-induced apoptosis of GC. The proliferation of GC ty -60cells was inhibited significantly in a time and dose-dependent manner by combined treatment of DDP with hesperetin. Hesperetin markedly increased DDP-induced apoptosis of GC cell lines. In a xenograft tumor mouse model, markedly better tumor suppression was observed after treatment with DDP plus hesperetin compared with that of either agent alone. Additionally, the combination of DDP and hesperetin remarkably increased the expression levels of phosphatase and tensin homolog (PTEN) and Cytochrome C (Cyt C), and significantly decreased the levels of phosphorylated protein kinase B (p-AKT) and CyclinD1. DDP and hesperetin also induced significant increases in apoptosis inducing factor (AIF), BCL2 associated X, apoptosis regulator (BAX), cleaved caspase-9, and cleaved caspase-3, and decreased B-cell lymphoma 2 (BCL2), caspase-9, and caspase-3 levels. Thus, we demonstrated that hesperetin could inhibit the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT signaling pathway and induce the mitochondrial pathway via upregulating PTEN expression, thereby significantly enhancing DDP’s anti-tumor effect on GC. Hesperetin is a potential chemotherapeutic agent for GC and merits further clinical investigation.

Enzymatic Metabolism of Flavonoids by Gut Microbiota and Its Impact on Gastrointestinal Cancer

“…In an in vivo and in vitro study, the results provided strong evidence that hesperidin enhances antitumor effects on gastric cancer by regulating PI3K/AKT signaling pathway through the upregulation of PTEN expression. In addition, a combinatory therapy of cisplatin with hesperidin could enhance the clinical outcome [120]. Additionally, luteolin can inhibit cellular proliferation by regulating PI3K, AKT and mTOR signaling pathways, which play a key role in the progression and development of gastric cancer [132].…”

Analysis of metabolites in young and mature Docynia delavayi (Franch.) Schneid leaves using UPLC-ESI-MS/MS

“…In our study, both young and mature leaves having their own unique metabolites. Differential metabolite analysis showed that most of the 12 metabolites present only in mature leaves have anti-tumor, anti-cancer, antioxidant, anti-inflammatory, anti-osteoporotic, anti-allergy, and other effects, which have high development value ( Bernatova, 2018 ; Chen et al, 2020 ; García-Lafuente et al, 2009 ; He et al, 2020 ; Ke et al, 2019 ; Kim et al, 2004 ; Li et al, 2017 ; Wei et al, 2019 ; Li et al, 2019 ).…”

Exploration of the Modulatory Property Mechanism of ELeng Capsule in the Treatment of Endometriosis Using Transcriptomics Combined With Systems Network Pharmacology

“…Limonin could induce apoptosis, thereby affecting the growth of SNU449 and HCT-15 tumor cells (Rahman et al, 2015). Hesperetin could promote cisplatininduced apoptosis in gastric cancer through upregulating the expression of tensin homolog (PTEN) (He et al, 2020). Naringin and its aglycone naringenin have shown anti-carcinogenic activities through cell signal transduction pathways in cancer (JAK-STAT pathway, PI3-kinase/Akt/ mTOR pathway, Notch pathway, NF-κB and cox-2 pathway, Wnt pathway, MAPK-ERK pathway, TGF-β pathway) (Memariani et al, 2020).…”