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Pan xiao
1. Evodiamine isolated from Evodia rutaecarpa as human
topoisomerase catalytic inhibitor
Xiaobei Pan1
, Janet M. Hartley2
, John A. Hartley2
, Kenneth N White1
,
Zhengtao Wang1,3
, S. W. Annie Bligh1
1
Institute for Health Research and Policy, London Metropolitan University, 166-220 Holloway Road, London N7 8DB, UK
2
Cancer Research UK Drug-DNA Interactions Research Group, UCL Cancer Institute, University College London, Paul O’Gorman Building, London, UK
3
The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese
Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Zhangjiang Hi-tech Park, Shanghai 201210, China
Introduction
Topoisomerase (Fig. 1) is an enzyme, which
can relieve torsional stress in DNA.
Topoisomerase I and II cleave the single
and double stranded DNA, respectively.
Since camptothecin was found as a
topoisomerase inhibitor, a number of semi-
synthetic compounds were successfully
developed and used to treat cancer.
Evodia rutaecarpa (Fig. 2) is a Chinese
herbal medicinal plant that has been used to
treat gastrointestinal disorders, bacterial
infection & inflammation-related disorders.
Evodiamine isolated from Evodia rutaecarpa
is cytotoxic to several cancer cell lines.
Aims and Objectives
To isolate quinoline alkaloids from the Evodia and structure elucidation
To study their potential cytotoxicity, inhibitory activity of topoisomerase I and
II, and catalytic mechanisms.
Methods
Alkaloids were isolated using reverse-phase HPLC and the structures were
elucidated by 1-D, 2-D NMR spectroscopy and mass spectrometry.
Their cytotoxicities were determined using MTT-based assay.
Topoisomerase (Topo) inhibitory activities were studied using Topo I relaxation
and Topo II decatanation assay.
Comet assay and cell cycle distribution study were carried out by flow
cytometry.
Results and Discussion
Eight alkaloids were isolated from Evodia, of which evodiamine (Fig. 3)
showed the most potent activity against human leukemia K562 and THP-1
cell lines (IC50 34.35 µM and 90.87 µM respectively.)
Evodiamine is an inhibitor for both human Topo I and Topo II (Fig. 4).
It did not induce DNA strand breaks at the cellular level (Fig. 5) and
arrested cell growth at the G2/M phase in the cell cycle.
N
H
N
N
O2
3
5
6
78
9
10
11
12
13
15
16
17
18
19
20
21
H
H3C
Conclusion
Evodiamine was found to be a dual inhibitor for both topoisomerase I and II
with potent cytotoxicity against human leukemia cell lines.
Figure 1. Structure of topoisomerase
Figure 2. Evodia rutaecarpa
Figure 3. Structure of Evodiamine
Figure 4. IC50 of evodiamine against human Topo I
(A, C) using relaxation assay and Topo II (B, D)
using decatanation assayFigure 5. The comet assay did not detect DNA
strand breaks induced by evodiamine
Acknowledgement
X.Pan thanks the Department of Human Science at London Metropolitan University for a student bursary.