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

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Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

H1 is an effectively and potential agent in reversing Pgp-mediated MDR by inhibiting the transport function and expression of Pgp.

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Acknowledgments

This work was supported by Grants (No. 30630069) from China National Natural Sciences Foundation.

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Authors and Affiliations

  1. Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, 100050, Beijing, China

    Ning Wei, Hua Sun & Gengtao Liu

  2. Department of Medicinal Natural Products, West China College of Pharmacy, Sichuan University, 610064, Chengdu, China

    Fengpeng Wang

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  1. Ning Wei
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  2. Hua Sun
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  3. Fengpeng Wang
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  4. Gengtao Liu
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Correspondence to Gengtao Liu.

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Wei, N., Sun, H., Wang, F. et al. H1, a novel derivative of tetrandrine reverse P-glycoprotein-mediated multidrug resistance by inhibiting transport function and expression of P-glycoprotein. Cancer Chemother Pharmacol 67, 1017–1025 (2011). https://doi.org/10.1007/s00280-010-1397-7

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  • DOI: https://doi.org/10.1007/s00280-010-1397-7

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