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      Reversal Effects of Components from the Fruits of Illicium simonsii on Human Adriamycin-resistant MCF-7 and 5-Fluorouracil-resistant Bel7402 Cells : REVERSAL EFFECTS OF ILLICIUM SIMONSII

      1 , 2 , 1
      Phytotherapy Research
      Wiley

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          Abstract

          Twenty-one compounds including seven characteristic sesquiterpene lactones were isolated from Illicium simonsii and screened in vitro for their potential to restore the sensitivity of Adriamycin (ADR) resistant breast cancer cells (MCF-7/ADR) and 5-fluorouracil-resistant hepatocellular carcinoma cells (Bel7402/5-FU) to ADR and 5-fluorouracil, respectively. These compounds were found to be non-toxic to a panel of tumour cell lines: human breast cancer cells (MCF-7), cervical cancer cells (HeLa), hepatic liver carcinoma cells (HepG-2, Bel7402) and gastric carcinoma cells (BGC-823, SGC-7901). Five compounds showed an obvious decrease in the IC(50) of doxorubicin in MCF-7/ADR and four compounds sensitized Bel7402/5-FU to 5-fluorouracil at non-toxic concentrations. The relationship between the structure of these non-cytotoxic substances and their multidrug-resistant (MDR) reversal abilities was investigated by principal component analysis (PCA) of the reversing fold (RF) values of these compounds and their calculated molecular descriptors of the tested substances. No correlations were found between the reversal potencies of these compounds to the two MDR cells. Compounds with lower polarity generally had stronger sensitizing ability to the P-glycoprotein (Pgp) overexpressed MCF-7/ADR cells. On the other hand, higher hydrophilic compounds seemed to exhibit a stronger reversal effect to the MDR-associated protein (MRP) overexpressed Bel7402/5-FU cell line. Our findings favoured further investigations on the active substances and the underlying mechanisms.

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          Recent advances in the discovery of flavonoids and analogs with high-affinity binding to P-glycoprotein responsible for cancer cell multidrug resistance.

          P-glycoprotein (P-gp) is a plasma membrane glycoprotein that confers multidrug resistance on cells by virtue of its ability to exclude cytotoxic drugs in an ATP-dependent manner. The most commonly considered hypothesis is that P-gp acts as an ATP-driven drug-export pump, the mechanism of which is not understood in detail. Therefore, a tremendous effort is being made to find out modulator molecules to inhibit P-gp. We have been developing flavonoid derivatives as a new class of promising modulators using a new in vitro rational-screening assay based on measurements of the binding-affinity toward the C-terminal nucleotide-binding domain (NBD2) of P-gp. This review is focused on our results obtained with a variety of flavonoids. Structure-activity relationships of flavonoids as potential MDR modulators are reported. Copyright 2002 Wiley Periodicals, Inc. Med Res Rev, 22, No. 5, 512-529, 2002; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/med.10015
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            Essential features of the P-glycoprotein pharmacophore as defined by a series of reserpine analogs that modulate multidrug resistance.

            We have shown previously that reserpine is an effective "modulator" of P-glycoprotein-associated multidrug resistance (MDR). In addition to enhancing drug cytotoxicity in our multidrug-resistant human leukemia cell line, CEM/VLB100, reserpine strongly competes with a photoactivatible analog of vinblastine, N-(p-azido-3-[125I]iodosalicyl)-N'-(beta-aminoethyl)vindesine, for binding to P-glycoprotein. We also demonstrated previously that there are three substructural domains present in many compounds that modulate P-glycoprotein-associated MDR: a basic nitrogen atom and two planar aromatic rings. In the present study, we wished to test more rigorously the hypothesis that not only are these domains necessary for modulators of MDR but also they must exist in an appropriate conformation. Reserpine is a modulator of MDR in which these domains are present in a well-defined conformation. Accordingly, we prepared eight compounds that vary the spatial orientation of these domains, using either naturally occurring reserpine or yohimbine as chemical templates. When tested for their ability to enhance the cytotoxic activity of natural product antitumor drugs in CEM/VLB100 cells, five compounds that retained the pendant benzoyl function in an appropriate spatial orientation all modulated MDR. By contrast, compounds lacking this moiety failed to do so. These active modulators competed strongly with the 125I-labeled vinblastine analog for binding to P-glycoprotein in plasma membrane vesicles prepared from these cells. Conformational analysis using molecular mechanics revealed the structural similarities of the active modulators. Our results support the hypothesis that the relative disposition of aromatic rings and basic nitrogen atom is important for modulators of P-glycoprotein-associated MDR, and they suggest a ligand-receptor relationship for these agents. These results also provide direction for the definition of an MDR "pharmacophore."
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              Activity of Drugs from Traditional Chinese Medicine toward Sensitive and MDR1- or MRP1-Overexpressing Multidrug-Resistant Human CCRF-CEM Leukemia Cells

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                Author and article information

                Journal
                Phytotherapy Research
                Phytother. Res.
                Wiley
                0951418X
                April 2012
                April 2012
                September 23 2011
                : 26
                : 4
                : 562-567
                Affiliations
                [1 ]Department of Natural Medicinal Chemistry; China Pharmaceutical University; Nanjing; PR China
                [2 ]School of Traditional Chinese Pharmacy; China Pharmaceutical University; Nanjing; PR China
                Article
                10.1002/ptr.3599
                21953821
                8a6215e3-a2f5-49f9-9645-9130099dc4af
                © 2011

                http://doi.wiley.com/10.1002/tdm_license_1.1

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