Exploiting Plug-And-Play Electrochemistry for Drug Discovery

Gao, Lixia; Teng, Yong

doi:10.4155/fmc.16.8

Cited by 17 publications

(7 citation statements)

References 79 publications

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“…The half-period of free radical is only few seconds, therefore, detection of the short lifetime of free radicals particularly demands fast response of the analytical tool to the changes in concentration to obtain sufficient signal-to-noise ratios [35]. Electrochemical biosensors have become promising candidates for in situ analysis of free radicals [36]. We have successfully performed electrochemical biosensors to determine the intracellular oxidative balance in the PLX4032-treated melanoma cells [25].…”

Section: Discussionmentioning

confidence: 99%

FGF19/FGFR4 signaling contributes to the resistance of hepatocellular carcinoma to sorafenib

Gao

Wang

Tang

et al. 2017

J Exp Clin Cancer Res

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134

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BackgroundSorafenib, a multi-kinase inhibitor, is used as a standard therapy for advanced hepatocellular carcinoma (HCC). However, complete remission has not been achieved and the molecular basis of HCC resistance to sorafenib remains largely unknown. Previous studies have shown that fibroblast growth factor 19 (FGF19) expression correlates with tumor progression and poor prognosis of HCC. Here, we demonstrate the novel role of FGF19 in HCC resistance to sorafenib therapy.MethodsFGF19 Knockdown cells were achieved by lentiviral-mediated interference, and FGFR4 knockout cells were achieved by CRISPR-Cas9. Protein levels of FGF19, FGFR4 and c-PARP in various HCC cell lines were measured by Western blotting analysis. Cell viability was determined by MTS assay, apoptosis was determined by DAPI nuclear staining and Western blot of c-PRAP, and ROS generation was determined by DCFH-DA staining and electrochemical biosensor.ResultsWe showed that FGF19, when overexpressed, inhibited the effect of sorafenib on ROS generation and apoptosis in HCC. In contrast, loss of FGF19 or its receptor FGFR4 led to a remarkable increase in sorafenib-induced ROS generation and apoptosis. In addition, knockdown of FGF19 in sorafenib-resistant HCC cells significantly enhanced the sensitivity to sorafenib. Importantly, targeting FGF19/FGFR4 axis by ponatinib, a third-generation inhibitor of chronic myeloid leukemia, overcomes HCC resistance of sorafenib by enhancing ROS-associated apoptosis in sorafenib-treated HCC.ConclusionOur results provide the first evidence that inhibition of FGF19/FGFR4 signaling significantly overcomes sorafenib resistance in HCC. Co-treatment of ponatinib and sorafinib may represent an effective therapeutic approach for eradicating HCC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0478-9) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

FGF19/FGFR4 signaling contributes to the resistance of hepatocellular carcinoma to sorafenib

Gao

Wang

Tang

et al. 2017

J Exp Clin Cancer Res

Self Cite

134

100

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“…This method allowed researchers to detect short-lived metabolites [109]. Regarding electrochemistry, a powerful analytical technique for chemical analysis of living cells, biologically active molecules and metabolites, Gao et al [110] reviewed useful measurement tools such as the electrochemical biosensor, microfluidics and mass spectrometry for various fields of biology and medicine. Similarly, to the above drug detection, the same cell culture mode and detection method can be used for the determinations of pharmacokinetic parameters.…”

Section: Application Of Microfluidic Chips In Drug Metabolism Evaluamentioning

confidence: 99%

Application of microfluidic chip technology in pharmaceutical analysis: A review

Cui

Wang

2019

Journal of Pharmaceutical Analysis

272

140

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The development of pharmaceutical analytical methods represents one of the most significant aspects of drug development. Recent advances in microfabrication and microfluidics could provide new approaches for drug analysis, including drug screening, active testing and the study of metabolism. Microfluidic chip technologies, such as lab-on-a-chip technology, three-dimensional (3D) cell culture, organs-on-chip and droplet techniques, have all been developed rapidly. Microfluidic chips coupled with various kinds of detection techniques are suitable for the high-throughput screening, detection and mechanistic study of drugs. This review highlights the latest (2010–2018) microfluidic technology for drug analysis and discusses the potential future development in this field.

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“…* À Electrochemical detection of free radical levels released from cells was established in our previous work (10,25,26,30). Briefly, 5 Â 10 5 HCC cells were seeded in 6-well plates in the presence or absence of various ER stress inducers.…”

Section: Electrochemical Detection Of Omentioning

confidence: 99%

FGF19 Protects Hepatocellular Carcinoma Cells against Endoplasmic Reticulum Stress via Activation of FGFR4–GSK3β–Nrf2 Signaling

et al. 2017

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The tumor microenvironment induces endoplasmic reticulum (ER) stress in tumor cells, an event that can promote progression, but it is unknown how tumor cells adapt to this stress. In this study, we show that the fibroblast growth factor FGF19, a gene frequently amplified in hepatocellular carcinoma (HCC), facilitates a survival response to ER stress. Levels of FGF19 expression were increased in stressed HCC cells in culture and in a mouse xenograft model. Induction of ER stress required the transcription factor ATF4, which directly bound the FGF19 promoter. In cells where ER stress was induced, FGF19 overexpression promoted HCC cell survival and increased resistance to apoptosis, whereas FGF19 silencing counteracted these effects. Mechanistic investigations implicated glycogen synthase kinase-3β (GSK3β) in regulating nuclear accumulation of the stress-regulated transcription factor Nrf2 activated by FGF19. Our findings show how FGF19 provides a cytoprotective role against ER stress by activating a FGFR4-GSK3β-Nrf2 signaling cascade, with implications for targeting this signaling node as a candidate therapeutic regimen for HCC management. .

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Exploiting Plug-And-Play Electrochemistry for Drug Discovery

Cited by 17 publications

References 79 publications

FGF19/FGFR4 signaling contributes to the resistance of hepatocellular carcinoma to sorafenib

FGF19/FGFR4 signaling contributes to the resistance of hepatocellular carcinoma to sorafenib

Application of microfluidic chip technology in pharmaceutical analysis: A review

FGF19 Protects Hepatocellular Carcinoma Cells against Endoplasmic Reticulum Stress via Activation of FGFR4–GSK3β–Nrf2 Signaling

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