H6, a novel hederagenin derivative, reverses multidrug resistance in vitro and in vivo

Yanting Yang, Daokun Guan, Lei Lei, Jing Lu, Jia Qi Liu, Gangqiang Yang, Chunhong Yan, Rong G Zhai, Jingwei Tian, Yi Bi, Fenghua Fu, Hongbo Wang

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

Multidrug resistance (MDR) is a serious obstacle encountered in cancer treatment, in which the overexpression of P-glycoprotein (P-gp) plays an important role. Here, a novel α-hederagenin derivative, designated H6, was designed, synthesized and evaluated for its ability to reverse MDR. Our results showed that H6 could sensitize KBV and MCF7/T cells to paclitaxel and vincristine. Meanwhile, H6 could increase both rhodamine 123 and paclitaxel accumulation in MDR cells without affecting the expression of P-gp. Interestingly, siRNA knockdown of MDR1 further sensitized the cytotoxic activity of paclitaxel when co-administrated with H6. In addition, H6 could directly stimulate P-gp ATPase activity in vitro. Importantly, H6 enhanced the efficacy of paclitaxel against KBV cancer cell-derived xenograft tumors in nude mice. Finally, H6 showed high binding affinity with P-gp with a high docking score. Overall, we show H6 is a novel and potent MDR reversal agent, which has the potential to be administered in combination with conventional anticancer drugs.

Original languageEnglish (US)
Pages (from-to)98-105
Number of pages8
JournalToxicology and Applied Pharmacology
Volume341
DOIs
StatePublished - Feb 15 2018
Externally publishedYes

Keywords

  • H6
  • Molecular docking
  • Multidrug resistance
  • P-glycoprotein
  • α-Hederagenin

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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  • Cite this

    Yang, Y., Guan, D., Lei, L., Lu, J., Liu, J. Q., Yang, G., Yan, C., Zhai, R. G., Tian, J., Bi, Y., Fu, F., & Wang, H. (2018). H6, a novel hederagenin derivative, reverses multidrug resistance in vitro and in vivo. Toxicology and Applied Pharmacology, 341, 98-105. https://doi.org/10.1016/j.taap.2018.01.015