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

34 Citations (Scopus)

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

Fingerprint

Multiple Drug Resistance
P-Glycoprotein
Paclitaxel
Derivatives
Rhodamine 123
Neoplasms
Oncology
T-cells
MCF-7 Cells
Vincristine
Heterografts
Nude Mice
Small Interfering RNA
Adenosine Triphosphatases
Tumors
Cells
T-Lymphocytes
In Vitro Techniques
hederagenin
Pharmaceutical Preparations

Keywords

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

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Cite this

H6, a novel hederagenin derivative, reverses multidrug resistance in vitro and in vivo. / Yang, Yanting; Guan, Daokun; Lei, Lei; Lu, Jing; Liu, Jia Qi; Yang, Gangqiang; Yan, Chunhong; Zhai, Rong G; Tian, Jingwei; Bi, Yi; Fu, Fenghua; Wang, Hongbo.

In: Toxicology and Applied Pharmacology, Vol. 341, 15.02.2018, p. 98-105.

Research output: Contribution to journalArticle

Yang, Y, Guan, D, Lei, L, Lu, J, Liu, JQ, Yang, G, Yan, C, Zhai, RG, 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, vol. 341, pp. 98-105. https://doi.org/10.1016/j.taap.2018.01.015
Yang, Yanting ; Guan, Daokun ; Lei, Lei ; Lu, Jing ; Liu, Jia Qi ; Yang, Gangqiang ; Yan, Chunhong ; Zhai, Rong G ; Tian, Jingwei ; Bi, Yi ; Fu, Fenghua ; Wang, Hongbo. / H6, a novel hederagenin derivative, reverses multidrug resistance in vitro and in vivo. In: Toxicology and Applied Pharmacology. 2018 ; Vol. 341. pp. 98-105.
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