JOURNAL OF SHANDONG UNIVERSITY(NATURAL SCIENCE) ›› 2023, Vol. 58 ›› Issue (7): 32-36, 51.doi: 10.6040/j.issn.1671-9352.0.2022.256

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MDR mechanism of isoliquiritigenin and derivatives

Yunrong JING1,2,3,*(),Qiuju MA1,Yang CHEN1,Wenli LIU2,Wei ZHOU2,Linxiang ZHAO3   

  1. 1. College of Life Science and Technology, Mudanjiang Normal University, Mudanjiang 157011, Heilongjiang, China
    2. Jiangsu Tasly Diyi Pharmaceutical Co., Ltd., Huaian 223003, Jiangsu, China
    3. School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, China
  • Received:2022-04-29 Online:2023-07-20 Published:2023-07-05
  • Contact: Yunrong JING E-mail:swxjyr@126.com

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Abstract:

The structures of isoliquiritigenin derivatives, ISL-1 and ISL-2, were characterized and evaluated for their MDR reversal activity in vitro. Canine kidney cell MDCK-MDR1 model with high expression of P-gp was used to investigate their interaction with P-gp. The experimental results showed that isoliquiritigenin, ISL-1 and ISL-2 exhibited MDR reversal activity on breast cancer MDR cell line MDA435/LCC6 MDR in different levers. They can significantly inhibit the efflux of P-gp, which are weak substrates of P-gp. It is expected to become MDR reversal agents with high efficiency and low toxicity.

Key words: isoliquiritigenin, derivative, P-glycoprotein, multidrug resistance, reversal agent

CLC Number: 

  • R914.5

Fig.1

Structure of isoliquiritigenin and its derivatives, ISL-1 and ISL-2"

Table 1

MDR reversal activity of compounds on MDA435/LCC6 MDR cell to paclitaxel"

Test compound IC50(nmol/L) of paclitaxel Reversal factor
Control 137.58±0.21 —
Verapamil 34.24±0.12 4.0
ISL 47.26±0.16 2.9
ISL-1 29.33±0.18 4.7
ISL-2 31.05±0.25 4.4

Table 2

A-B and B-A Papp of digoxin, ISL, ISL-1 and ISL-2 across MDCK-WT and MDCK-MDR1 monolayers in the presence and absence of verapamil (100 μmol/L)"

Compounda Treatmentb MDCK-WT MDCK-MDR1
Papp(10-6 cm/s) Efflux ratio Papp(10-6 cm/s) Efflux ratioc
A-B B-A A-B B-A
ISL Control 1.09 3.08 2.82 0.47 5.02 10.68
Verapamil 1.48 2.96 2.00 1.13 4.49 3.97
ISL-1 Control 1.83 3.99 2.18 0.73 6.28 8.60
Verapamil 2.59 3.05 1.18 1.71 2.06 1.20
ISL-2 Control 1.55 3.46 2.23 0.58 4.89 8.43
Verapamil 2.16 2.27 1.05 1.82 2.36 1.30
Digoxin Control 0.36 9.01 25.02 0.44 27.79 63.16
Verapamil 0.39 1.08 2.77 2.08 2.89 1.39

Table 3

Permeability of digoxin in the presence and absence of test compounds"

Compound Treatmenta Papp (10-6 cm/s) Efflux ratio
A-B B-A
Samp-1 Samp-2 Mean Samp-1 Samp-2 Mean
Digoxin(5 μmol/L) Control 0.50 0.54 0.52 28.54 30.46 29.50 56.73
ISL 1.89 1.99 1.94 19.76 20.52 20.14 10.38
ISL-1 1.51 1.27 1.39 8.98 10.12 9.55 6.87
ISL-2 1.65 1.77 1.71 15.17 15.33 15.25 8.92
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