Reversal of P-glycoprotein-mediated multidrug resistance of cancer cells by five schizandrins isolated from the Chinese herb Fructus Schizandrae
Reversal of P-glycoprotein-mediated multidrug resistance of cancer cells by five schizandrins isolated from the Chinese herb Fructus Schizandrae
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DOI：
10.1007/s00280-008-0691-0
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发表时间：
2008-11-01
影响因子：
3
通讯作者：
Liu, Geng Tao
中科院分区：
文献类型：
--
作者：
Huang, Min;Jin, Jing;Liu, Geng Tao
目的五味子(FS)是中医常用的补品。近年来，FS被发现能显著改善慢性肝炎患者的肝功能障碍。本研究旨在探讨五味子乙素及其粗提物(LCC)在体内外对癌细胞多药耐药(MDR)的逆转作用。化学上，这5个五味子内酯是二苯并-(a，c)-环辛烯木脂素的衍生物，具有不同于任何已知的MDR逆转剂的结构。体外药敏、多柔比星(Dox)蓄积、P-糖蛋白和蛋白激酶C(PKC)表达及细胞凋亡率测定。结果5种化合物在25 mU M下均表现出不同程度的多药耐药逆转活性，其中五味子甲素(Sin A)的逆转作用最强。SIN A使KBv200细胞、MCF-7/Dox细胞和Bel7402细胞对VCR的耐药性分别逆转309倍、38倍和84倍。此外，Sin A还逆转了上述癌细胞对Dox的耐药性。25微克/毫升的LCC逆转KBv200细胞对VCR的耐药性619倍，MCF-7/Dox细胞181倍，人肝癌Bel7402细胞对VCR的天然耐药性1,563倍。此外，LCC及其活性成分Sin A有效地逆转了这些细胞对紫杉醇的交叉耐药性。Sin A和LCC均能显著增加MDR细胞内Dox蓄积，促进细胞凋亡，下调Pgp蛋白和总PKC的表达。共同管理LCC(P.O.)显著增强VCR的抑制作用(I.P.)结论LCC及其活性成分Sin A通过抑制Pgp和总PKC的功能和表达，对肿瘤细胞的多药耐药有明显的逆转作用。
Purpose 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.Methods 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).Results The tested five compounds at 25 mu M 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 mu g/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.Conclusions 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.