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Coniferyl Ferulate, a Strong Inhibitor of Glutathione S-Transferase Isolated from Radix Angelicae sinensis, Reverses Multidrug Resistance and Downregulates P-Glycoprotein.

ABSTRACT: Glutathione S-transferase (GST) is the key enzyme in multidrug resistance (MDR) of tumour. Inhibition of the expression or activity of GST has emerged as a promising therapeutic strategy for the reversal of MDR. Coniferyl ferulate (CF), isolated from the root of Angelica sinensis (Oliv.) Diels (Radix Angelicae sinensis, RAS), showed strong inhibition of human placental GST. Its 50% inhibition concentration (IC50) was 0.3? ? M, which was greater than a known GSTP1-1 inhibitor, ethacrynic acid (EA), using the established high-throughput screening model. Kinetic analysis and computational docking were used to examine the mechanism of GST inhibition by CF. Computational docking found that CF could be fully docked into the gorge of GSTP1-1. The further exploration of the mechanisms showed that CF was a reversible noncompetitive inhibitor with respect to GSH and CDNB, and it has much less cytotoxicity. Apoptosis and the expression of P-gp mRNA were evaluated in the MDR positive B-MD-C1 (ADR+/+) cell line to investigate the MDR reversal effect of CF. Moreover, CF showed strong apoptogenic activity and could markedly decrease the overexpressed P-gp. The results demonstrated that CF could inhibit GST activity in a concentration-dependent manner and showed a potential MDR reversal effect for antitumour adjuvant therapy.

SUBMITTER: Chen C

PROVIDER: S-EPMC3766616 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Coniferyl Ferulate, a Strong Inhibitor of Glutathione S-Transferase Isolated from Radix Angelicae sinensis, Reverses Multidrug Resistance and Downregulates P-Glycoprotein.

Chen Chang C Wu Chuanhong C Lu Xinhua X Yan Zhiyong Z Gao Jian J Zhao Hui H Li Shaojing S

Evidence-based complementary and alternative medicine : eCAM 20130824

Glutathione S-transferase (GST) is the key enzyme in multidrug resistance (MDR) of tumour. Inhibition of the expression or activity of GST has emerged as a promising therapeutic strategy for the reversal of MDR. Coniferyl ferulate (CF), isolated from the root of Angelica sinensis (Oliv.) Diels (Radix Angelicae sinensis, RAS), showed strong inhibition of human placental GST. Its 50% inhibition concentration (IC50) was 0.3 μ M, which was greater than a known GSTP1-1 inhibitor, ethacrynic acid (EA ...[more]

PMID: 24058374

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Project description:BACKGROUND:Radix Astragali and Radix Angelicae Sinensis are two herbs that compose Danggui Buxue Tang (an herbal formula for treatment of anemia diseases). In this study, we explored the molecular mechanism and effective targets to immune destruction of bone marrow (BM) cells treated with Radix Astragali, Radix Angelicae Sinensis or a combination of two agents. The potential synergic advantages of two herbs should also be explored. METHODS:The constituents of Radix Astragali and Radix Angelicae Sinensis were analyzed by high performance liquid chromatography-electrospray ionization/mass spectrometer system BM cells were separated from limbs of BALB/c mice, and immune destruction was induced with IFN-?. The percentages of hematopoietic stem cells (HSCs) and CD3+ T cells were detected by flow cytometry. The distribution of T-bet and changes in the combination of SAP and SLAM in BM cells were observed by immunofluorescence. Western blotting was used to assay the expression of key molecules of the eIF2 signaling pathway in BM cells. RESULTS:Seven constituents of Radix Astragali and six constituents of Radix Angelicae Sinensis were identified. The percentages of HSCs increased significantly after treatment with Radix Angelicae Sinensis, especially at high concentrations. The percentages of CD3+ T cells were significantly decreased after Radix Astragali and Radix Angelicae Sinensis treatment. However, the synergistic function of two-herb combinations was superior to that of the individual herbs alone. The distribution of T-bet in BM cells was decreased significantly after Radix Angelicae Sinensis treatment. The number of SLAM/SAP double-stained cells was increased significantly after Radix Astragali treatment at low concentrations. The phosphorylation levels of eIF2? were also reduced after Radix Astragali and Radix Angelicae Sinensis treatment. CONCLUSIONS:Radix Astragali and Radix Angelicae Sinensis could intervene in the immunologic balance of T lymphocytes, inhibit the apoptosis of BM cells induced by immune attack, restore the balance of the T cell immune response network and recover the hematopoietic function of HSCs. The synergistic effects of Radix Astragali and Radix Angelicae Sinensis were superior to those of each herb alone.

Dataset Information

Coniferyl Ferulate, a Strong Inhibitor of Glutathione S-Transferase Isolated from Radix Angelicae sinensis, Reverses Multidrug Resistance and Downregulates P-Glycoprotein.

Publications

Coniferyl Ferulate, a Strong Inhibitor of Glutathione S-Transferase Isolated from Radix Angelicae sinensis, Reverses Multidrug Resistance and Downregulates P-Glycoprotein.

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