H1, a novel derivative of tetrandrine reverse P-glycoprotein-mediated multidrug resistance by inhibiting transport function and expression of P-glycoprotein

Cancer Chemotherapy and Pharmacology
Ning WeiGeng Tao Liu

Abstract

H1 is a novel derivative of tetrandrine (Tet). Here we investigate the ability of H1 to reverse P-glycoprotein (Pgp)-mediated multidrug resistance (MDR) and its mechanisms. KBv200, MCF-7/adr and their parental sensitive cell lines KB, MCF-7 were used for reversal study. The intracellular accumulation and efflux studies with Pgp substrates of doxorubicin and rhodamine 123 were determined by flow cytometry. The expression of Pgp was investigated by Western blot and RT-PCR analysis. ATPase activity of Pgp was performed by Pgp-Glo(™) assay systems. The ubiquitination level of Pgp was determined by immunoprecipitation analysis. The effect of ERK1/2 on Pgp expression in KBv200 cells were investigated by RNA interference. H1 significantly potentiated the sensitivity of Pgp substrates in KBv200 and MCF-7/adr cells, but not in parental cells KB and MCF-7. H1 inhibited Pgp expression in KBv200 cells in a dose-dependent manner, but had no effect on MDR1 expression. Further studies showed that H1 prompted the degradation of Pgp and decreased Pgp protein half-life by enhancing the ubiquitination of Pgp, which may be related to downregulated MEK-ERK signal pathway. We also found H1 inhibited ATPase activity of Pgp in a dose-dependent manner....Continue Reading

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Citations

Feb 6, 2016·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Yidan LinXiangguo Liu
Sep 4, 2012·Journal of Controlled Release : Official Journal of the Controlled Release Society·Min HanJian-Qing Gao
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May 26, 2012·Biochimie·Carole SeidelMarc Diederich
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Apr 10, 2019·Anti-cancer Agents in Medicinal Chemistry·Nana NiuZhengbao Zhao
Sep 14, 2019·Anti-cancer Drugs·Xiangyan CuiXin Wang

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