Anti-tumor and reversing MDR effects of conglobatin a macrolide dilactone compound
Anti-tumor and reversing MDR effects of conglobatin a macrolide dilactone compound作者机构：School of Pharmacy Fujian Provincial Key Laboratory of Natural Medicine Pharmacology Fujian Medical University
出 版 物：《中国药理学与毒理学杂志》 (Chinese Journal of Pharmacology and Toxicology)
年 卷 期：2019年第10期
页 面：894-894页
学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学]
主 题：conglobatin Hsp90 inhibitor anti-tumor effect
摘 要：OBJECTIVE To investigate macrolide dilactone compound conglobatin anti-tumor, reversing multi-drug resistance（MDR） effects and their mechanisms of action in vitro and in vivo. METHODS MTT assay was used to assess the proliferation-inhibiting effect of conglobatin alone or combination with lapatinib, and used to detected the reversal MDR effect of conglobatin on ABCB1 or ABCG2 overexpressing cells. Flow cytometry was used to examined the effects of conglobatin induced cell apoptosis and intracellular accumulation of doxorubicin（DOX, adriamycin, adr）/Rhodamine 123（Rho 123）, efflux of doxorubicin. Chemproteomics, computational docking,immunoprecipitation and Western blotting were taken to investigate the antitumor mechanism of *** antitumor activity and reversal MDR effect of conglobatin in vivo were evaluated with xenograftes *** Conglobatin significantly inhibited the proliferation of hepatocellular carcinoma cell QGY7703 and breast cancer cell SKBR3（the IC50 values ranging from12 to 19 μmol·L-1 at 48 h exposure）, and induced apoptosis in a dose-dependent manner. Its inducing apoptosis was associated with down-regulating the expression of antiapoptotic protein Bcl-2 and up-regulating the expression of pro-apoptotic protein Bax, and then promoting the cleavage of caspase and PARP. The combination of conglobatin and lapatinib showed synergistic effects on inhibiting cell proliferation, inducing cell apoptosis, which was associate with its reducing the total and activated HER3 levels in HER2+breast cancer cells. Conglobatin 100 mg·kg-1 significantly reduced the tumor volume of QGY7703 and SKBR3 and conglobatin combining with lapatinib 100 mg·kg-1 significantly enhanced the anti-tumor effect in vivo. Further research found that conglobatin could directly bind to the N-terminal of Hsp90 then disturb forming a complex of Hsp90, Cdc37 and clients, and dissociate clients from Hsp90 subsequently induce proteasome-dependent degradation of the clients such
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