Ursolic acid sensitized colon cancer cells to chemotherapy under hypoxia by inhibiting MDR1 through HIF-1α

Shan, Jianzhen; Xuan, Yanyan; Zhang, Qi; Huang, Jianjin

doi:10.1631/jzus.b1600266

Cited by 29 publications

(12 citation statements)

References 33 publications

(39 reference statements)

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“…2D and G ). These findings are consistent with the observations of previous studies on HIF-1α, where HIF-1α downregulation was reported to inhibit the expression levels of VEGF and MDR1 in cancer cells ( 17 , 33 ). Notably, LV-H721 infection led to HIF-1 α knockout in the SMMC-7721 ×enograft tissues ( Fig.…”

Section: Discussionsupporting

confidence: 93%

CRISPR/Cas9‑mediated hypoxia inducible factor‑1α knockout enhances the antitumor effect of transarterial embolization in hepatocellular carcinoma

et al. 2018

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Transarterial embolization (TAE) is a palliative option commonly used for the treatment of advanced, unresectable hepatocellular carcinoma (HCC). However, patient prognosis in regards to overall survival has not improved with this method, mainly due to hypoxia-inducible factor-1α (HIF-1α)-induced angiogenesis and invasiveness. Thus, it is hypothesized that HIF-1α may be an ideal knockout target for the treatment of HCC in combination with TAE. Thus, in the present study, HIF-1α knockout was conducted in human liver cancer SMMC-7721 cells and a xenograft HCC model was established using a lentivirus-mediated CRISPR/Cas system (LV-Cas) with small guide RNA-721 (LV-H721). Furthermore, hepatic artery ligation (HAL) was used to mimic human transarterial chemoembolization in mice. The results revealed that HIF-1α was highly expressed in both HCC patient tissues and SMMC-7721-induced tumor tissues. The HIF-1α knockout in SMMC-7721 cells significantly suppressed cell invasiveness and migration, and induced cell apoptosis under CoCl2-mimicking hypoxic conditions. Compared with the control groups, HAL + LV-H721 inhibited SMMC-7721 tumor growth in orthotopic HCC and markedly prolonged the survival of HCC-bearing mice, which was accompanied by a lower CD31 expression (tumor angiogenesis) and increased apoptosis in the tumor cells. These findings demonstrated a valuable antitumor synergism in combining CRISPR/Cas9-mediated HIF-1α knockout with TAE in mice and highlighted the possibility that HIF-1α may be an effective therapeutic knockout target in combination with TAE for HCC treatment.

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Section: Discussionsupporting

confidence: 93%

CRISPR/Cas9‑mediated hypoxia inducible factor‑1α knockout enhances the antitumor effect of transarterial embolization in hepatocellular carcinoma

et al. 2018

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“…The angiogenic factor VEGFA is produced by active synovial fibroblasts and has been implicated in the pathogenesis of RA, being one of its most important biomarkers ( Taylor, 2002 ). Studies have revealed the chemosensitizing effects of ursolic acid in colon cancer ( Shan et al, 2016 ) and the protective effects of paeoniflorin against oxidative injury ( Song et al, 2017 ), both via suppression of VEGF signaling. Taken together, our results are in agreement with previous research showing the compound-target relationship between ursolic acid/paeoniflorin and each of LGALS3, STAT3, and VEGFA.…”

Section: Discussionmentioning

confidence: 99%

Evaluating the Therapeutic Mechanisms of Selected Active Compounds in Cornus Officinalis and Paeonia Lactiflora in Rheumatoid Arthritis via Network Pharmacology Analysis

Huang

et al. 2021

Front. Pharmacol.

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Cornus officinalis Sieb et. Zucc and Paeonia lactiflora Pall. have exhibited favorable therapeutic effects against rheumatoid arthritis (RA), but the specific mechanisms of their active compounds remain unclear. The aim of this study was to comprehensively analyze the therapeutic mechanisms of selected active compounds in Cornus officinalis (loganin, ursolic acid, and morroniside) and Paeonia lactiflora (paeoniflorin and albiflorin) via network pharmacology. The pharmacological properties of the five active compounds were evaluated and their potential target genes were identified by database screening. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional analysis were performed to determine the enriched molecular pathways associated with the active compounds. Using network pharmacology tools, eight genes (IL1β, VEGFA, STAT3, TP53, IL6, TNF, FOS, and LGALS3) were identified as common targets between RA and the five active compounds. Molecular docking simulation revealed the compound-target relationship between the five active compounds and three selected targets from the eight common ones (LGALS3, STAT3, and VEGFA). The compound-target relationships were subsequently validated via preliminary in vivo experiments in a rat model of collagen-induced arthritis. Rats subjected to collagen-induced arthritis showed increased protein expression of LGALS3, STAT3, and VEGFA in synovial tissues. However, treatment using Cornus officinalis or/and Paeonia lactiflora, as well as their most drug-like active compounds (ursolic acid or/and paeoniflorin, respectively, identified based on pharmacological properties), attenuated the expression of these three targets, as previously predicted. Collectively, network pharmacology allowed the pharmacological and molecular roles of Cornus officinalis and Paeonia lactiflora to be systematically revealed, further establishing them as important candidate drugs in the treatment and management of RA.

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“…Ursolic acid can inhibit the expression of newborn VEGF and inhibit the accumulation of HIF-1 α and the expression of the MDR1 gene and protein under hypoxia. It has a sensitizing effect on chemotherapy of colon cancer cells [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

Investigating the Multitarget Pharmacological Mechanism of Ursolic Acid Acting on Colon Cancer: A Network Pharmacology Approach

Zhao

Leng

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Objective. To explore the mechanisms of ursolic acid for treating colon cancer based on network pharmacology. Method. In this study, the potential targets of ursolic acid against colon cancer were predicted and screened through the TCMSP, SYMMAP, Drug Bank, UNI-PROT, and DISGENET databases. The protein interaction (PPI) network was constructed based on the STRING database, and graphs were drawn with the help of Cytoscape software. GO and KEGG enrichment analyses were performed on the targets by using the DAVID database for biological information annotation. Results. Ursolic acid has 113 targets in the treatment of colon cancer. The core targets included interleukin-6 (IL-6), mitogen-activated protein kinase 3 (MAPK3), vascular endothelial growth factor receptor (VEGFA), prostaglandin endoperoxide synthase 2 (PTGS2), caspase-3 (CASP3), mitogen-activated protein kinase 8 (MAPK8), tumor necrosis factor (TNF), cyclin D1 (CCND1), JUN, signal transducer and transcriptional activator 3 (STAT3), and other targets. The first 10 pathways related to colon cancer were screened out. The main signaling pathways included the TNF signaling pathway and the AGE-RAGE signaling pathway in diabetic complications and human colon cancer infections. Conclusion. This study revealed that ursolic acid played a multitarget and multichannel antitumor role by inhibiting the proliferation of tumor cells, inducing apoptosis, and enhancing antiangiogenesis.

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Ursolic acid sensitized colon cancer cells to chemotherapy under hypoxia by inhibiting MDR1 through HIF-1α

Cited by 29 publications

References 33 publications

CRISPR/Cas9‑mediated hypoxia inducible factor‑1α knockout enhances the antitumor effect of transarterial embolization in hepatocellular carcinoma

CRISPR/Cas9‑mediated hypoxia inducible factor‑1α knockout enhances the antitumor effect of transarterial embolization in hepatocellular carcinoma

Evaluating the Therapeutic Mechanisms of Selected Active Compounds in Cornus Officinalis and Paeonia Lactiflora in Rheumatoid Arthritis via Network Pharmacology Analysis

Investigating the Multitarget Pharmacological Mechanism of Ursolic Acid Acting on Colon Cancer: A Network Pharmacology Approach

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