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Qian X.-K.,Institute of Cancer Stem Cell | Wang P.,CAS Dalian Institute of Chemical Physics | Xia Y.-L.,CAS Dalian Institute of Chemical Physics | Dou T.-Y.,CAS Dalian Institute of Chemical Physics | And 6 more authors.
Sensors and Actuators, B: Chemical | Year: 2016

Catechol-O-methyltransferase (COMT), one of the most important phase II drug metabolizing enzymes, plays important roles in the metabolism of endogenous and xenobiotic catechols. In this study, a highly selective fluorescent probe for sensing activities of catechol-O-methyltransferase in complex biological samples was discovered and well characterized. Under physiological conditions, COMT selectively catalyzes the conversion of the probe (7,8-dihydroxy-4-methylcoumarin, DHMC) to 7-hydroxy-8-methoxy-4-methylcoumarin (HMMC), which brings a strong turn-on fluorescence signal at 520 nm. The probe substrate has been used for monitoring the real activities of COMT in complex biological samples, as well as for rapid screening of potential COMT inhibitors which are useful in the treatment of Parkinson's diseases Furthermore, the probe has been successfully used to monitor endogenous COMT in living cells for the first time, and the results demonstrate that DHMC is cell membrane permeable and low toxic to the cells. All these features of DHMC suggested that this probe holds great promise for COMT-related regulation and inhibition assays in drug discovery, as well as for further investigation on the biological functions of COMT in living cells. © 2016 Elsevier B.V. Source


Zheng F.-M.,Sun Yat Sen University | Zheng F.-M.,Dalian Medical University | Zheng F.-M.,Institute of Cancer Stem Cell | Long Z.-J.,Sun Yat Sen University | And 19 more authors.
Molecular Cancer Therapeutics | Year: 2014

Chemoresistance is a major cause of cancer treatment failure. Tumor-initiating cells (TIC) have attracted a considerable amount of attention due to their role in chemoresistance and tumor recurrence. Here, we evaluated the smallmolecule Aurora kinase inhibitor AKI603 as a novel agent against TICs in breast cancer. AKI603 significantly inhibited Aurora-A (AurA) kinase and induced cell-cycle arrest. In addition, the intragastric administration of AKI603 reduced xenograft tumor growth. Interestingly, we found that breast cancer cells that were resistant to epirubicin expressed a high level of activated AurA and also have a high CD24Low/CD44High TIC population. The inhibition of AurA kinase by AKI603 abolished the epirubicin-induced enrichment of TICs. Moreover, AKI603 suppressed the capacity of cells to form mammosphere and also suppressed the expression of self-renewal genes (β-catenin, γ-Myc, Sox2, and Oct4). Thus, our work suggests the potential clinical use of the small molecule Aurora kinase inhibitor AKI603 to overcome drug resistance induced by conventional chemotherapeutics in breast cancer. ©2014 AACR. Source

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