Geniposide reverses multidrug resistance in vitro and in vivo by inhibiting the efflux function and expression of P-glycoprotein

Hu, Huang; Xue-nong, Zhang; Huang, Zhixiong; Zhang, Ye; Zhou, Zhi

doi:10.3892/etm.2016.4011

Cited by 14 publications

(16 citation statements)

References 22 publications

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“…However, the response of breast cancer patients to ADR is very poor, with no significant increase in patient survival. Previously, numerous mechanisms of ADR resistance, especially the rate of drug influx or efflux, have been identified [26-28]. In this study, we demonstrate a novel mechanism of chemoresistance by which cancer cells increase glycolytic flux.…”

Section: Discussionmentioning

confidence: 69%

FGFR4 Links Glucose Metabolism and Chemotherapy Resistance in Breast Cancer

Xu¹,

Chen²,

Yang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Poor response to chemotherapy leads to the relapse and metastatic progression of tumors. Reprogrammed glucose metabolism is one of the important hallmarks of cancer that facilitates cancer cell survival, proliferation and chemoresistance. However, the precise fate of glucose metabolism and its role in therapy responsiveness in cancers remains largely unexplored. Methods: The glycolytic phenotype of doxorubicin (ADR)-resistant breast cancer cells and their parental cells was assessed by measuring glucose uptake, lactate release, and extracellular acidification rate (ECAR). Protein expression was detected by Western blotting analysis and mRNA expression was detected using q-PCR. Cell survival ratio was determined by the cell counting kit 8 assay. The role of fibroblast growth factor receptor 4 (FGFR4) in glycolysis, chemoresistance, and the underlying mechanisms were studied by using gene expression microarray and short hairpin RNA-mediated gene knockdown. Results: We found that glycolytic flux are increased in two doxorubicin (ADR)-resistant breast cancer cell lines compared with their parental wild type cells, as demonstrated by increased glucose uptake, lactate release, and extracellular acidification rate (ECAR). By gene expression microarray, we identified FGFR4 as a critical modulator of ADR resistance and enhanced glucose metabolism. Genetic silencing of FGFR4 increased the chemosensitivity and suppressed the enhanced glycolytic flux in ADR-resistant cells. Mechanistically, activation of FGFR4 signaling in ADR-resistant cells led to the phosphorylation of FGF receptor substrate 2 (FRS2) and further activated the downstream MAPK/ERK signaling. Pharmacological inhibition of FGFR4-FRS2-ERK signaling pathway significantly blocked the chemoresistant and glycolytic phenotypes of ADR-resistant cells. Conclusion: Our findings suggest that high levels of FGFR4 can increase glucose metabolism and lead to chemoresistance in breast cancer and reveal the mechanistic basis for targeting FGFR4 as a therapeutic opportunity for chemoresistant tumors.

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Section: Discussionmentioning

confidence: 69%

FGFR4 Links Glucose Metabolism and Chemotherapy Resistance in Breast Cancer

Xu¹,

Chen²,

Yang³

et al. 2018

Cell Physiol Biochem

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“…This compound has the IUPAC name methyl (1S,4aS,7aS)-7-(hydroxymethyl)-1-[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-1,4a,5,7a-tetrahydrocyclopenta[c]pyran-4-carboxylate and the common name geniposide and is one of the major iridoid glycosides of gardenia fruit. It was previously shown to inhibit 5-lipoxygenase [33] and the tumor-promoting factor P-glycoprotein [34] and have anti-angiogenic activity [35] and potential antiasthma properties [36]. Additionally, geniposide was shown recently to protect against sepsis-induced myocardial dysfunction by activating AMPKα to suppress myocardial reactive oxygen species (ROS) accumulation [37].…”

Section: Resultsmentioning

confidence: 99%

Virtual Screening of Natural Products against Type II Transmembrane Serine Protease (TMPRSS2), the Priming Agent of Coronavirus 2 (SARS-CoV-2)

et al. 2020

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused about 2 million infections and is responsible for more than 100,000 deaths worldwide. To date, there is no specific drug registered to combat the disease it causes, named coronavirus disease 2019 . In the current study, we used an in silico approach to screen natural compounds to find potent inhibitors of the host enzyme transmembrane protease serine 2 (TMPRSS2). This enzyme facilitates viral particle entry into host cells, and its inhibition blocks virus fusion with angiotensin-converting enzyme 2 (ACE2). This, in turn, restricts SARS-CoV-2 pathogenesis. A three-dimensional structure of TMPRSS2 was built using SWISS-MODEL and validated by RAMPAGE. The natural compounds library Natural Product Activity and Species Source (NPASS), containing 30,927 compounds, was screened against the target protein. Two techniques were used in the Molecular Operating Environment (MOE) for this purpose, i.e., a ligand-based pharmacophore approach and a molecular docking-based screening. In total, 2140 compounds with pharmacophoric features were retained using the first approach. Using the second approach, 85 compounds with molecular docking comparable to or greater than that of the standard inhibitor (camostat mesylate) were identified. The top 12 compounds with the most favorable structural features were studied for physicochemical and ADMET (absorption, distribution, metabolism, excretion, toxicity) properties. The low-molecular-weight compound NPC306344 showed significant interaction with the active site residues of TMPRSS2, with a binding energy score of −14.69. Further in vitro and in vivo validation is needed to study and develop an anti-COVID-19 drug based on the structures of the most promising compounds identified in this study.

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“…[ 14 ] It has been proved to play outstanding antitumor activities on human oral squamous carcinoma, osteosarcoma, and glioma through inhibiting cell proliferation and promoting cell apoptosis. [ 20‐22 ] Besides that, Galvez et al [ 49 ] indicated that geniposide was able to exert anticancer activity on other tumors such as renal adenocarcinoma, breast adenocarcinoma, and melanoma by stabilizing covalent attachment of the topoisomerase I subunits to DNA at sites of DNA strand breaks.…”

Section: Discussionmentioning

confidence: 99%

“…[ 19 ] For antitumor activity, Qian et al [ 20 ] indicated that geniposide could inhibit cell proliferation and induce cell apoptosis of human oral squamous carcinoma HSC‐3 cells. Huang et al [ 21 ] proved that geniposide could reverse multidrug resistance of tumor therapy in vivo and in vitro by suppressing the P‐glycoprotein activity. For central nervous system tumors, previous studies reported that geniposide could inhibit glioma C6 cell metastasis by suppressing matrix metalloproteinase‐2 (MMP‐2) expression and induce cell apoptosis by activating mitogen‐activated protein kinase (MAPK)‐mediated activator protein‐1 (AP‐1).…”

Section: Introductionmentioning

confidence: 99%

Retracted: Geniposide exhibits anticancer activity to medulloblastoma cells by downregulating microRNA‐373

2020

J Biochem & Molecular Tox

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Background: Medulloblastoma is a common tumor originates from central nervous system in children with metastatic potential. Geniposide is the major active ingredient separated from the fruit of Gardenia jasminoides Ellis. Herein, we tested the possible anticancer activity of geniposide on human medulloblastoma cells, as well as the potential underlying molecular mechanisms.Methods: Firstly, followed by geniposide incubation, cell viability, proliferation, apoptosis, migration, and invasion of medulloblastoma Daoy cells, along with microRNA-373 (miR-373) expression were tested, respectively. Then, the influences of miR-373 overexpression in the reduction of medulloblastoma cell proliferation, migration, and invasion and the elevation of apoptosis, triggered by geniposide treatment, were reinvestigated. Finally, the Ras/Raf/MEK/ERK pathway activity was analyzed. Results: Geniposide treatment inhibited medulloblastoma cell viability, proliferation, migration, and invasion, but promoted cell apoptosis. Surprisingly, miR-373 expression in medulloblastoma cells was obviously downregulated by geniposide treatment. miR-373 overexpression reversed the effects of geniposide on Daoy cells. Furthermore, geniposide hindered the Ras/Raf/MEK/ERK pathway by downregulating miR-373 expression. Conclusion: Geniposide exhibited anticancer activity on human medulloblastoma cells and blocked Ras/Raf/MEK/ERK pathway by downregulating miR-373 expression. K E Y W O R D S cell metastasis, cell proliferation, geniposide, medulloblastoma, microRNA-373, Ras/Raf/MEK/ ERK pathway

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Geniposide reverses multidrug resistance in vitro and in vivo by inhibiting the efflux function and expression of P-glycoprotein

Cited by 14 publications

References 22 publications

FGFR4 Links Glucose Metabolism and Chemotherapy Resistance in Breast Cancer

FGFR4 Links Glucose Metabolism and Chemotherapy Resistance in Breast Cancer

Virtual Screening of Natural Products against Type II Transmembrane Serine Protease (TMPRSS2), the Priming Agent of Coronavirus 2 (SARS-CoV-2)

Retracted: Geniposide exhibits anticancer activity to medulloblastoma cells by downregulating microRNA‐373

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