Reversal of P-glycoprotein-mediated multidrug resistance of cancer cells by five schizandrins isolated from the Chinese herb Fructus Schizandrae

Division of Oncology, Department of Internal Medicine, Stanford University, Stanford, CA 94301, USA.
Cancer Chemotherapy and Pharmacology (Impact Factor: 2.57). 03/2008; 62(6):1015-26. DOI: 10.1007/s00280-008-0691-0
Source: PubMed

ABSTRACT Fructus Schizandrae (FS) is commonly used as a tonic in traditional Chinese medicine. Recently, FS was found to significantly improve liver dysfunction in chronic hepatitis patients. The present study was to assess the reversal effect of five schizandrins and crude extract from FS (named LCC) on multidrug resistance (MDR) of cancer cells, both in vitro and in vivo. Chemically, the five schizandins are derivatives of dibenzo-(a, c)-cyclooctene lignan with distinct structures differing from any known MDR reversal agents.
A panel of sensitive and resistant cancer cell lines were treated with various concentrations of LCC and schizandrins. Drug sensitivity, accumulation of Doxorubicin (Dox), expression of P-glycoprotein and protein kinase C (PKC), and apoptosis were determined in vitro. The in vivo effect was tested in nude mice grafted with sensitive and resistant human epidermal cancer cell line to vincristine (VCR) (KB, KBv200).
The tested five compounds at 25 muM showed various levels of MDR reversal activity, of which, schizandrin A (Sin A) was the most potent one. Sin A reversed VCR resistance in KBv200 cells, MCF-7/Dox cells and Bel7402 cells by 309-, 38-, and 84-folds, respectively. Also, Sin A reversed the resistance of Dox in the above cancer cell lines. LCC at 25 mug/ml reversed VCR resistance by 619-folds in KBv200, 181-folds in MCF-7/Dox cell line, and 1,563-folds in innate resistance of human hepatic cellular carcinoma Bel7402 cells to VCR. Furthermore, LCC and its active component Sin A potently reversed the cross-resistance to paclitaxel in those cell lines. Both Sin A and LCC markedly increased intracellular Dox accumulation and enhanced apoptosis, down-regulated Pgp protein and mRNA and total PKC expression in MDR cells. Coadministration of LCC (p.o.) significantly potentiated the inhibitory effect of VCR (i.p.) on tumor growth in nude mice bearing KBv200 xenograft.
The LCC and its active component Sin A have remarkable reversal effect on MDR in cancer cells by inhibition of both the function and expression of Pgp and total PKC.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In recent years, the cancer stem cell (CSC) theory has provided a new angle in the research of cancer, and has gradually gained significance. According to this theory, the multiple drug resistance (MDR) of cancer is most likely due to the resistance of CSCs, and a significant quantity of research has been carried out into the MDR mechanisms of CSC. Over time, some of these mechanisms have been gradually accepted, including ATP-binding cassette transporters, aldehyde dehydrogenase, the CSC microenvironment and epithelial to mesenchymal transition. In the present review, we summarize these mechanisms in detail and review possible appropriate therapy plans against CSCs based on CSC theory.
    Experimental and therapeutic medicine 02/2015; 9(2):289-293. DOI:10.3892/etm.2014.2141 · 0.94 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The chemistry of natural products has emerged as an extremely important area of contemporary research owing to their profound biological activities, complex molecular architecture with challenging stereochemistry and potential for use as medicine. Searches for efficient synthetic procedures for natural products, drugs, and materials with economical and ecological advantages are important areas of current research interest. This article describes the isolation, bioactivity and synthesis of several natural products and drugs by employing coinage metal-catalyzed/mediated reaction/strategy either in a sequential or a domino fashion. We have made an attempt to summarize the progress made in the area from 2008 onwards.
    RSC Advances 01/2014; 4(16):8085. DOI:10.1039/c3ra44336a · 3.71 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Preclinical ResearchSchisandrae Chinensis Fructus (SCF), the fruit of Schisandra chinensis (Turcz.) Baill. (family Schisandraceae) is traditionally used as a tonic and antidiabetic agent in Asia. In this study, SCF was investigated for its effects on sodium glucose cotransporters 1 and 2 (SGLT 1 and 2) expressed in a COS-7 cell line for its specificity in inhibiting SGLT2, which is a novel mechanism to screen for potential antidiabetic agents. Using a bioassay-guided fractionation, we then tried to isolate and identify the active fraction(s)/component(s). The ethanol extract of SCF at a concentration of 1 mg/mL significantly inhibited 89% of SGLT1 and 73% of SGLT2 activities in a [14C]-α-methyl-d-glucopyranoside ([14C]-AMG) uptake assay. Fractionation of the ethanol extract yielded nine fractions, of which F8, at a concentration of 1 mg/mL, was specific in inhibiting SGLT 2 (42% inhibition, P < 0.001), without inhibiting SGLT 1. Using LC/MS-MS, three compounds, deoxyschisandrin, schisandrin B (γ-schisandrin) and schisandrin were identified in F8 and their amounts quantified. However, subsequent evaluation in the [14C]-AMG uptake assay showed that these three compounds failed to inhibit SGLT 2 activity indicating that the SGLT active component(s) from SCF have yet to be identified.
    Drug Development Research 12/2014; DOI:10.1002/ddr.21233 · 0.73 Impact Factor