Studies on the anti cancer potential of sesquiterpene lactone parthenolide 1

STUDIES ON THE ANTI-CANCER POTENTIAL OF THE
SESQUITERPENE LACTONE PARTHENOLIDE

ZHANG SIYUAN
(B. Med. Peking University, P.R.China)

A THESIS SUBMITTED FOR
THE DEGREE OF DOCTOR OF PHILOSOPHY

DEPARTMENT OF COMMUNITY, OCCUPATIONAL
AND FAMILY MEDICINE
NATIONAL UNIVERSITY OF SINGPAORE

2005


ACKNOWLEGEMENTS

I would like to gratefully acknowledge my supervisors, Prof. Ong Choon-Nam and
Dr. Shen Han-Ming, for their consistent and enthusiastic professional guidance
throughout my study. They have brought me into this exciting biological world and, more
importantly, they provided me many valuable approaches in doing research: Prof. Ong
who consistently emphasizes and reminds me of the fundamental theories and overall
strategy of my study; Dr. Shen who is outspoken in his insightful comments and
suggestions with great inspirations. I am also grateful for their patience and kindness
throughout my study. All of these are invaluable to me in my whole life.
It was also a great pleasure for me to work in the big family of Department of
Community, Occupational, and Family Medicine in the last four years. I was surrounded
by a group of friendly people who have helped me carry out my study smoothly. I would
like to thank Prof. David Koh for his general guidance and support during my study in
COFM. A special thank goes to our laboratory staffs: Mr. Ong Her Yam who have

provided me with an excellent working environment in COFM and Mr. Ong Yeong Bing
who had provided me with dedicated assistance in the animal study. I am also grateful to
my bench mates Dr. Peter Colin Rose, Mr. Won Yen Kim, Mr. Shi Ran Xin, Ms. Huang
Qing for their useful comments and suggestions on my study. I would also like to thank
the staff in Clinical Research Center, NUS, for their technical assistance on flow
cytometry and confocal microscopy.
A deep appreciation goes out to my wife, Zhao Min, whose dedicated love,
understanding and support made this thesis possible.

ii


TABLE OF CONTENTS
Acknowledgements

ii

Table of Contents

iii

Summary

x

List of Figures

xii

Abbreviations

xv

List of Publications

xix

CHAPTER 1
INTRODUCTION
1.1

2

Parthenolide
1.1.1 Introduction: feverfew and Parthenolide

2

1.1.2 Chemical structure, metabolism and bioactivities of parthenolide

2

1.1.2.1 Chemistry: sesquiterpene lactones and parthenolide

2

1.1.2.2 Transportation in cell system and bioavailability

4

1.1.2.3 Bioactivities of parthenolide

5

1.1.3 The molecular mechanisms involved in the bioactivities of parthenolide

6

1.1.3.1 Effects on NF-κB signaling

6

1.1.3.2 Effects on inflammatory-related molecules

8

1.1.3.3 Effects on Mitogen-activated protein kinase (MAPK) pathway

12

1.1.3.4 Effects on Janus Kinase (JAK)-Signal Transducers and Activators of
Transcription (STAT) pathway and cytokine signaling
1.1.3.5 Effects on cell proliferation and induction of apoptosis

13

1.1.3.6 Effects on cell cycle regulation

15

14

1.1.4 in vivo study of parthenolide

16

iii


1.1.5 Toxicity and adverse side effects
1.2

17
17

Oxidative stress, biothiols and intracellular redox balance.
1.2.1 Reactive Oxygen Species

17

1.2.1.1 Definition

17

1.2.1.2 Sources of ROS

18

1.2.2 Biothiols

19

1.2.2.1 Definition

19

1.2.2.2 Biological properties and metabolism

20

1.2.3 Anti-oxidant defense system

21

1.2.4 Redox balance

22

1.2.5 Biological consequences of redox imbalance

23

1.2.5.1 Lipid peroxidation
1.2.5.2 DNA damage

24

1.2.5.3 Signal transduction

24

1.2.5.4 Apoptosis
1.3

23

25
25

Apoptosis and Cancer
1.3.1 Introduction

25

1.3.2 Cell death receptors

27

1.3.3 Caspases

28

1.3.4 Bcl-2 protein family and mitochondria

30

1.3.5 Other important regulators in apoptosis

34

1.3.5.1 Thiols and intracellular redox balance in apoptosis

34

1.3.5.2 Endoplasmic reticulum (ER) stress and Ca2+ in apoptosis

35

1.3.5.3 MAPK in apoptosis

36

iv


1.3.6 Dysregulated apoptosis in cancer
1.4

37
39

TNF and NF-κB activation
1.4.1 TNF superfamily and TNF-induced apoptosis

40

1.4.2 TNFα-induced NF-κB activation and suppression of apoptosis by NF-κB
activation
1.5
Cyclooxygenase, prostaglandin and cancer

41
44

1.5.1 Cyclooxygenase and prostaglandins metabolism
1.5.2 Cyclooxygenase-2: an important cancer promoter

46

1.5.2.1 Epidemiological and experimental evidence

46

1.5.2.2 Mechanisms of the carcinogenic property of cyclooxygenase-2
1.6

44

47
49

Objectives of the study

CHAPTER 2
THE CRITICAL ROLE OF INTRACELLULAR THIOLS AND
Ca2+ IN PARTHENOLIDE-INDUCED CELL DEATH
2.1

Introduction

52

2.2

Materials and Methods

53

2.2.1 Reagents

53

2.2.2 Cell culture and treatments

54

2.2.3 Determination of intracellular GSH and GSSG content

54

2.2.4 Measurement of intracellular protein thiols

55

2.2.5 Measurement of intracellular ROS formation and Calcium release

56

2.2.6 Western blot

57

2.2.7 DNA content assay

58

2.2.8 TUNEL assay

58

v


2.2.9 Statistical analysis
2.3

59
59

Results
2.3.1 Parthenolide-induced intracellular thiols depletion
2.3.2 Effects of NAC and BSO on parthenolide-induced intracellular thiols
depletion
2.3.3 Effects of parthenolide on overall intracellular ROS level

60

2.3.4 Effects of parthenolide on cytosolic calcium level

64

2.3.5 Effects of cellular redox status on parthenolide-induced apoptosis
2.4

59

68

64

75

Discussion

CHAPTER 3
INVOLVEMENT OF PROAPOPTOTIC BCL-2 FAMILY
MEMBERS IN PARTHENOLIDE-INDUCED MITOCHONDRIAL
DYSFUNCTION AND APOPTOSIS
3.1

Introduction

81

3.2

Materials and methods

83

3.2.1 Chemicals and reagents

83

3.2.2 Cell culture and treatment

83

3.2.3 Detection of Apoptosis

84

3.2.4 Western blot

84

3.2.5 Transfection and Immunostaining

85

3.2.6 Measurement of mitochondrial membrane potential (MMP)

86

3.2.7 Cell subfractionation and detection of release of mitochondrial proteins

86

3.2.8 Protein cross-linking

87

3.2.9 In vitro assay for caspase 3-like activity

88

3.2.10 Statistical analysis

88

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3.3

88

Results
3.3.1 Activation of caspase cascade by parthenolide in COLO205 cells
3.3.2 Parthenolide-induced Bid cleavage following caspase 8 activation

91

3.3.3 Bax conformational changes and mitochondrial translocation in
parthenolide-treated cells
3.3.4 Enhanced Bak protein level and Bak oligomerization in parthenolidetreated cells
3.3.5 Loss of MMP and release of mitochondrial proteins
3.4

88

92
97
97
102

Discussion

CHAPTER 4
SUPPRESSED NF-κB AND SUSTAINED JNK ACTIVATION
CONTRIBUTE TO THE SENSITIZATION EFFECT OF
PARTHENOLIDE TO TNFα-INDUCED APOPTOSIS IN HUMAN
CANCER CELLS
4.1

Introduction

108

4.2

Materials and methods

110

4.2.1 Chemicals, reagents, and plasmids

110

4.2.2 Cell culture and treatments

111

4.2.3 Cell viability test and detection of apoptosis

111

4.2.4 Preparation of cytosolic and nuclear extracts

113

4.2.5 Electrophoretic mobility shift assay (EMSA)

113

4.2.6 Transient transfections and luciferase reporter gene assay

114

4.2.7 IKK and JNK in vitro kinase assay

115

4.2.8 Co-immunoprecipitation and western blot (WB)

116

4.2.9 Statistics

117

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4.3

117

Results
4.3.1 Parthenolide sensitizes cancer cells to TNFα-mediated apoptosis

117

4.3.2 Parthenolide inhibits NF-κB activation

120

4.3.3 Parthenolide prevents recruitment of the IKK complex to TNF receptor 1

121

4.3.4 Pretreatment of parthenolide leads to a sustained JNK activation in TNFαtreated cells
4.3.5 Sustained JNK activation plays an important role in the sensitization effect
of parthenolide to TNFα-mediated apoptosis
4.4
Discussion

127
132
133

CHAPTER 5
PARTHENOLIDE SUPPRESSES THE GROWTH OF
COLORECTAL CANCER XENOGRAFTS BY INDUCING
APOPTOSIS AND TARGETING CYCLOOXYGENASE-2
5.1

Introduction

139

5.2

Materials and methods

140

5.2.1 Chemicals and reagents
5.2.2 Cell culture and treatment

141

5.2.3 Cell growth inhibition and induction of apoptosis

141

5.2.4 Determination of COX-2 protein level and PGE2 level in vitro

142

5.2.5 In vivo nude mice implantation and treatment

142

5.2.6 Evaluation of BrdU incorporation in HCA-7 xenografts

143

5.2.7 Evaluation of apoptotic cell death in HCA-7 xenografts

144

5.2.8 Evaluation of COX-2 expression in HCA-7 xenografts

145

5.2.9 Evaluation of PGE2 level in vivo

146

5.2.10 Statistics
5.3

140

147

Results

147

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5.3.1 Cells with higher expression level of COX-2 are more susceptible to
parthenolide-induced cytotoxicity
5.3.2 Direct effects of parthenolide on COX-2 expression and PGE2 production
5.3.3 Parthenolide inhibits HCA-7 cell growth in vivo

153

5.3.4 Parthenolide induces apoptotic cell death in HCA-7 xenografts

159

5.3.5 Parthenolide inhibits COX-2 expression in HCA7 xenografts

159

5.3.6 Effects of parthenolide feeding on PGE2 level in vivo
5.4

147

163

152

163

Discussion

CHAPTER 6
GENERAL DISCUSSION AND CONCLUSION
Anti-cancer potential of parthenolide – thiol-depletion induced
disruption of cellular homeostasis
6.1.1 Parthenolide depletes cellular thiol and induces oxidative stress

170

6.1.2 Parthenolide-induced thiol depletion is associated with ER stress and
calcium burst
6.2
Anti-cancer potential of parthenolide – induction of apoptosis

173

6.2.1 Proapoptotic approach: direct induction of apoptosis by parthenolide

177

6.2.2 Apoptosis-permissive approach: potentializing cancer cells in response to
apoptosis induced by other chemotherapeutic agents
6.3
Anti-cancer property parthenolide – an in vivo nude mice xenografts
model
6.4
Limitations in current study and further directions

180

6.5

188

6.1

Conclusions

171

175

184
187

CHAPTER 7
REFERENCES

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SUMMARY
Parthenolide is the major sesquiterpene lactone responsible for the bioactivities of
Feverfew (Tanacetum parthenium), a traditional herbal medicine which has been used in
treatment of fever, migraine and arthritis for centuries. This compound is known to have
potent anti-inflammatory properties, which is executed by inhibiting major inflammationresponsive pathways, such as nuclear factor kappa-B (NF-κB) pathway, mitogenactivated protein kinase (MAPK) signaling and signal transducers and activators of
transcription (STAT) signaling pathway, blocking the expression of pro-inflammatory
cytokines. However, its anti-cancer properties are less studied. Thus, the main objective
of this study is to systematically investigate the anti-cancer properties of parthenolide.

The following investigations have been conducted: (i) the effects of parthenolide on
intracellular redox balance and the biological consequences of parthenolide-induced
thiol-depletion; (ii) the molecular mechanisms involved in parthenolide-induced
apoptosis; (iii) the anti-cancer potential of parthenolide by investigating its sensitization
ability to cancer cells in response to death receptor ligands induced apoptosis; (iv) the
anti-cancer property of parthenolide using an in vivo nude mice xenografts model.
Firstly, parthenolide induced a rapid depletion of biothiols and a concomitant
increase of ROS level which resulted in the disruption of intracellular redox balance. As a
consequence of unbalanced redox status, a severe endoplasmic reticulum (ER) stress was
observed, as evidenced by an increased expression of ER stress marker protein GRP78
and cellular calcium burst. All these changes led to a typical apoptotic cell death. To
further elucidate the mechanisms of parthenolide-induced apoptosis, a series of
experiments were conducted by focusing on the changes of mitochondria and Bcl-2
protein family members. It was demonstrated that parthenolide triggered the activation of

x


the caspase cascade. The changes of pro-apoptotic Bcl-2 family members including Bid
cleavage, Bax translocation and Bak dimerization were also found to play a role in
promoting parthenolide-induced apoptosis. In addition to the direct induction of
apoptosis, parthenolide also significantly sensitized various cancer cells in response to
TNFα-mediated apoptosis. The inhibition of NF-κB activation and induction of a
sustained JNK activation were proved to be the major mechanisms contributing to
parthenolide’s sensitization effect. To further validate the anti-cancer property of
parthenolide, an in vivo nude mice xenograft study was conducted. It was observed that
parthenolide-feeding significantly reduced the tumor formation by inhibiting the cancer
cell proliferation and inducing apoptosis. Parthenolide also significantly suppressed
cyclooxygenase-2 (COX-2) expression and COX-2-derived prostaglandin synthesis,
suggesting COX-2 may be an important molecular target of parthenolide.

In conclusion, the present study provides experimental evidence from both in vitro
cell culture and in vivo animal model demonstrating the anti-cancer properties of
parthenolide. These novel findings provide a new insight of the parthenoldie’s bioactivity
which may help to develop it into a potential anti-cancer drug in the near future.

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LIST OF FIGURES

Figure 1.1 Feverfew and chemical structure of parthenolide

3

Figure 1.2 Formation of parthenolide-thiol adducts

4

Figure 1.3 Fenton and metal catalyzed Haber-Weiss reaction

18

Figure 1.4 Thiol and disulfides

20

Figure 1.5 Cycling of biothiols

21

Figure 1.6 Glutathione (GSH) synthesis

22

Figure 1.7 Mitochondria and Bcl-2 family: the central point of apoptosis
signaling

29

Figure 1.8 TNFα-induced apoptosis and NF-κB activation

43

Figure 1.9 Cyclooxygenase and prostaglandin synthesis

46

Figure 1.10 Cyclooxgenase-2 promotes cancer formation

48

Figure 2.1 Effects of parthenolide on intracellular GSH concentration

61

Figure 2.2 Effects of parthenolide on intracellular protein thiols

62

Figure 2.3 Effects of NAC and BSO on intracellular GSH of parthenolide

treated COLO205 cells

63

Figure 2.4 Effects of NAC and BSO on intracellular protein thiols of
parthenolide treated COLO205 cells

63

Figure 2.5 Effects of parthenolide on overall intracellular ROS level
detected by carboxy-H2DCFDA

65

Figure 2.6 Effects of NAC and BSO on parthenolide-induced overall
intracellular ROS level

66

Figure 2.7 Effects of parthenolide on intracellular calcium level detected by
Fluo-3 AM

67

Figure 2.8 Effects of NAC and BSO on parthenolide induced intracellular
calcium release detected by Fluo-3 AM

69

xii

Figure 2.9 Parthenolide-induced expression of ER stress protein GRP78
detected by western blot

70

Figure 2.10 Parthenolide-induced apoptotic cell death detected by sub-G1
assay

71

Figure 2.11 Parthenolide-induced apoptotic cell death detected by TUNEL
assay

72

Figure 2.12 Different effects of NAC and BSO on parthenolide-induced
apoptotic cell death detected by sub-G1 and TUNEL assay

73

Figure 2.13 Different effects of pro-treatment (pre) or co-treatment (co) of
NAC/BSO on parthenolide-induced apoptotic cell death
detected by sub-G1 assay

74

Figure 3.1 Parthenolide-induced initiator caspase activation

89

Figure 3.2 Parthenolide-induced effector caspase activation

90

Figure 3.3 Parthenolide-induced PARP cleavage and apoptotic cell death

93

Figure 3.4 Prevention of parthenolide-induced apoptotic cell death by
caspase inhibitors

94

Figure 3.5 Prevention of parthenolide-induced apoptotic cell death by
caspase inhibitors (continued)

95

Figure 3.6 Parthenolide-induced Bid cleavage

96

Figure 3.7 Bax conformational changes and mitochondrial translocation

98

Figure 3.8 Parthenolide-induced Bak overexpression and oligomerization

99

Figure 3.9 Parthenolide-induced changes of mitochondrial membrane
potential (MMP)

100

Figure 3.10 Parthenolide-induced release of mitochondrial proapoptotic
proteins

101

Figure 4.1 Parthenolide sensitizes cancer cells to TNFα-mediated apoptosis

118

Figure 4.2 TNFα-induced apoptotic cell death detected by TUNEL assay

119

Figure 4.3 Quantification of apoptotic cell death measured by DAPI
staining in different human cancer cell lines

122

Figure 4.4 Parthenolide inhibits transcriptional activity of NF-κB
determined by luciferase reporter gene assay

123

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Figure 4.5 Parthenolide inhibits p65 nuclear translocation and DNA binding

124

Figure 4.6 Parthenolide inhibits TNFα-induced IKK activation and IκB
degradation

125

Figure 4.7 Parthenolide interrupts the recruitment of IKKs to TNFR1 and
TRAF2

126

Figure 4.8 Parthenolide induces a sustained JNK activation after TNFα
stimulation

128

Figure 4.9 JNK inhibitor SP600125 prevents the sensitization effects of
parthenolide to TNFα-mediated apoptosis

129

Figure 4.10 Overexpression of DN-JNK1 and DN-JNK2 as well as CrmA
suppresses parthenolide’s sensitization effects to TNFαmediated apoptosis

130

Figure 4.11 Overexpression of DN-JNK1 and DN-JNK2 suppresses
parthenolide’s sensitization effects to TNFα-mediated apoptosis
(continued)

131

Figure 5.1 Differential expression of cyclooxygenase and different PGE2
synthesis levels of two colorectal cancer cell lines HCA-7 and
HCT116

148

Figure 5.2 Different sensitivity of HCA-7 and HCT-116 to parthenolideinduced cytotoxicity

149

Figure 5.3 Different sensitivity of HCA-7 and HCT-116 to parthenolideinduced apoptosis

150

Figure 5.4 Inhibition of COX-2 expression by parthenolide-treatment in
HCA-7 cells

151

Figure 5.5 Inhibition of PGE2 synthesis by parthenolide treatment in HCA-7
cells

154

Figure 5.6 Effect of dietary feeding of the parthenolide on HCA-7 xenograft
tumor growth in athymic female nude mice

155-156

Figure 5.7 Effect of parthenolide on cell proliferation within HCA-7
xenograft tumors examined by BrdU incorporation

157

Figure 5.8 Parthenolide-induced apoptosis within HCA-7 xenograft tumors
examined by TUNEL immunohistochemistry staining

158

Figure 5.9 Effects of parthenolide on COX-2 expression in HCA-7
xenograft tumors examined by COX-2 immunohistochemistry
staining
Figure 5.10 Effects of parthenolide feeding on PGE2 level in vivo

Figure 6.1 Mechanisms involved in parthenolide (PN)-induced apoptosis

160-161

162
185

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ABBREVIATIONS

5-HT

5-Hydroxytryptamine

8-OHdG

8-hydroxy-2’- deoxyguanosine

Act D

actinomycin D

AICD

activation-induced-cell-death

AIF

apoptosis-inducing factor

ANT

adenylate translocator

Apaf-1

apoptosis-activating factor 1

ASK1

apoptosis signal-regulating kinase 1

ATP

adenosine triphosphate

Bak

Bcl-2 homologous antagonist

Bax

Bcl-2 associated X protein

BH3

Bcl-2 homology domain 3

Bid

BH3-interacting domain death agonist

BrdU

5-Bromo-2'-deoxy-uridine

BSA

bovine serum albumin

BSO

buthionine sulfoximine

CAM

cell adhesion molecule

CARD

caspase activation and recruitment domain

c-FLIP

cellular FLICE inhibitory protein

CHX

cycloheximide

COX

cyclooxygenase

CsA

cyclosporin A

Cyto c

cytochrome c

DCFH-DA

2',7'-dichlorodihydrofluorescein diacetate

DED

death effector domain

DEVD-CHO

Asp-Glu-Val-Asp-CHO

DISC

death-inducing signaling complex

DMSO

dimethyl sulfoxide

DR

death receptor

DSS

disuccinimidyl subernate

xv


DTNB

5,5-dithiobis-2-nitrobenzonic acid

DTT

dithiothreitol

EDTA

ethylene diamine-tetra-acetic acid

EIA

enzyme immunoassay

ER

endoplasmic reticulum

ERK

extracellular regulated protein kinase

ETC

electron transport chain

FADD

Fas-associated death domain protein

FBS

Fetal bovine serum

FILP

FLICE inhibitory protein

G3PDH

glyceraldehydes-3-phosphate dehydrogenase

GRase

glutathione reductase

GSH

reduced glutathione

GSSG

oxidized glutathione/ glutathione disulphide

IAPs

inhibitors of apoptosis

ICAM-1

intracellular cell adhesion molecule-1

IKC

IKK complex

IKK

IκB kinase

IL

interleukin

INFγ

interferon-γ

iNOS

inducible isoform of nitric oxide synthase

IκB

NF-κB inhibitory protein

JAK

Janus kinase

JNK

c-Jun N-terminal kinase

LPS

lipopolysaccharide

MAPK

mitogen-activated protein kinase

MDA

malondialdehyde

MEKK1

mitogen-activated protein kinase 1

MEKK3

mitogen-activated protein kinase 3

MKK

MAPK kinase

MMP

mitochondrial membrane potential

MPT

mitochondrial permeability transition

MRP

multidrug resistance transporter P-glycoprotein

xvi


MTD

maximal tolerated dose

MTT
NAC

3,(4,5-dimethylthiazol-2-yl)2,5-diphenyl-tetrazolium bromide

N-acetylcysteine

NADH

nicotinamide-adenine dinucleotide (reduced)

NADPH

nicotinamide-adenine dinucleotide phosphate (reduced)

NEM

N-ethylmaleimide

NF-κB

nuclear factor-kappaB

NLS

nuclear localization sequence

NO

nitric oxide

NSAIDS

non-steroidal anti-inflammatory drugs

OPT

o-phthalaldehyde

PARP

poly(ADP-ribose) polymerase

PG

prostaglandin

PI

propidium iodide

PMSF

phenylmethylsulfonyl fluoride

PT

permeability transition

PTPC

membrane permeability transition pore complex

PUFA

polyunsaturated fatty acid

Rh-123

rhodamine 123

ROS

reactive oxygen species

RT-PCR

reverse transcription polymerase chain reaction

SDS

sodium dodecyl sulfate

SH

sulphydryl

Smac

second mitochondrial activator of caspases

SOD

superoxide dismutase

STAT

signal transducers and activators of transcription

tBid

truncated Bid

TNFR1

TNF receptor 1

TNFα

tumor necrosis factor α

TPA

12-o-tetradecanoylphorbol-13-acetate

TRADD

TNF-R1-associated death domain protein

TRAF2

TNF receptor associated factor 2

TRAIL

TNF-related apoptosis-inducing ligand

xvii


TUNEL

TdT-mediated dUTP nick end labeling

UV

ultraviolet light

VCAM-1

vascular cell adhesion molecule-1

VDAC

voltage-dependent anion channel

XIAP

X-linked inhibitor of apoptosis protein

Z-IETD-FMK

benzyloxycarbonyl-Ile-Glu-Thr-Asp-(OMe) fluoromethyl ketone

Z-VAD-FMK

benzyloxycarbonyl-Val-Ala-Asp-(OMe) fluoromethyl ketone

γ-GCS

γ-glutamyl cysteine synthestase

Δψ m

mitochondrial membrane potential

xviii


LIST OF PUBLICATIONS
Zhang,S., Ong,C.N., and Shen,H.M. (2004). Critical roles of intracellular thiols and
calcium in parthenolide-induced apoptosis in human colorectal cancer cells. Cancer Lett.
208, 143-153.
Zhang,S., Ong,C.N., and Shen,H.M. (2004). Involvement of proapoptotic Bcl-2 family
members in parthenolide-induced mitochondrial dysfunction and apoptosis. Cancer Lett.
211, 175-188.
Zhang,S., Lin,Z.N., Yang,C.F., Shi,X., Ong,C.N., and Shen,H.M. (2004). Suppressed
NF-κB and sustained JNK activation contribute to the sensitization effect of parthenolide
to TNFα-induced apoptosis in human cancer cells. Carcinogenesis.25, 2191-2199.
Zhang,S., Won, Y.K., Ong,C.N., and Shen,H.M. (2004). Anti-cancer properties of
sesquiterpene lactones, Curr Med Chem. (In press)
Zhang,S., Ong,C.N., and Shen,H.M. (2004). Parthenolide suppresses the growth of
colorectal cancer xenografts by targeting cyclooxygenase-2 and inducing apoptosis.
(manuscript in preparation)
Abstracts:

Zhang,S., Ong,C.N., and Shen,H.M.(2003). Mitochondrial dysfunction mediates
parthenolide-induced apoptosis in human colorectal cells. Proceedings of the 94th Annual
Meeting of American Association for Cancer Research.
Zhang,S., Lin,Z.N., Yang,C.F., Shi,X., Ong,C.N., and Shen,H.M. (2004). Suppressed
NF-κB and sustained JNK activation contribute to the sensitization effect of parthenolide
to TNFα-induced apoptosis in human cancer cells. Proceedings of first ShangHai
Symposium on Signal Transduction and Cancer.

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