Transcript Slide 1

Group members
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Mrs. Prisna Pianjing
Ms. Monta Thammasatta
Ms. Kunnika Changwichan
Mrs. Indra Gurung
Ms. Davong Oumavong
Hepatocellular carcinoma (HCC)
Cancer arise from hepatocyte
It is found at peak age 50-70 years and
commonly occur in men
Major causes are Hepatitis viral infection and
Aflatoxin B1
HCC is the fifth leading cause of cancer
mortality in the world
Its incidence is highest in sub-Saharan Africa,
China, southern Asia, and Japan.
http://www.healingdaily.com/conditions/cirrhos
is
Sign and symptoms
- Loss of appetite and weight
-Abdominal pain, especially in the upper right
part of the abdomen, that may extend into
back and shoulder
- Nausea and vomiting
- General weakness and fatigue
- An enlarged liver
- Abdominal swelling (ascites)
-A yellow discoloration of skin and the
whites of eyes (jaundice)
Mechanism of
hepatocarcinogenesis
• Chronic hepatitis and cirrhosis commonly
occur in preneoplastic stage
• Hepatitis B core antigen (HBcAg),Hepatitis
Bsurface antigen (HBsAg),HBx
• Hepatitis C virus
• DNA Adduct by AflatoxinB1
• Combination
Diagnosis of HCC
• The prognosis for patients with HCC after
diagnosis is poor.
• The early detection of HCC might therefore be a
mean to improve survival prospect.
• Done by basic laboratory evaluation and
conducts every 6-12 months in patients at risk.
• Ultrasonography, MRI and CT scan can be used
as detection for HCC associate with blood
evaluation.
How to detect HCC earlier….
Development of Hepatocellular carcinoma
Treatment of HCC
• Surgical
Resection,Transplantation
- Non surgical
Chemotherapy
Prognosis of HCC
Depends on the size of the tumor and
the extent of liver function impairment
The life expectancy of HCC patients is hard to predict because of
the high possibility of postoperative recurrence.
Poor prognosis is result from many factors:
Poor early detection
Treatment is high cost and often recurrence
Harmful infection and difficult to treat
Exposure of risk factors are difficult to avoid
That why we must focus on prevention
Chemoprevention & Chemo intervention
The most important public health and medical practice
is prevention of cancer
“Prevent is better than cure”
Chemopreventive agents are any and all natural or
synthetic compound that can Inhibit, suppress,
or reverse the development and progression of cancer
Chemo preventive agents can be administered as dietary
component in food dietary supplements or
pharmaceuticals preparations.
Prevention
Therapy
Chemo preventive
agent
- High Risk
- Non-toxic
- Altered Food
- Molecular markers
- Combination
CPA
CPA : Chemopreventive agents
CTA : Chemotherapeutic agents
-Cancer Patients
-Toxicity acceptable
- Molecular marker
-Synthetic drugs
-Combination with CPA
CTA
Which way we can do in case of HCC…….
- Enhance detoxification
- Prevent premalignant cell
- Early detection
What are we going to do…….
Stimulate detoxificatin
aflatoxinB1 removed
Enhance production of Phase II enzyme
Phase II enzyme for removal
Aflatoxin B1
The enzyme conjugate Aflatoxin B1 for excreting
out via urine is..
Glutathione S-transferase (GSTs)
Aflatoxin-N-acetylcysteine
To enhance this reaction, GST must be activated
Sulphoraphan and curcuminoid have high potency
to induce phase II enzyme….
We’ve known that these two substances can
induce GST......How…
Transcriptional control to phase II gene is achieve by
the binding of Nrf2 (nuclear factor erythroid2-relate factor)
to consensus activate antioxidant response element (ARE)
Keap1 repress Nf2 but if it dissociate from Keap1
ARE will be activated and GST will be produced
www.ptinr.com/data/articlefiles/39-sprout.jpg
www.communitygarden.org.au/.../root/tumeric.jpg
Broccoli : A cruciferous vegetable that has high
potency in prevention of cancer….How!!
It contains a large numbers of phytochemical:
The most significant is Glucosinolate
It is a precursor of 2 groups of active compounds
Isothiocyanate and Indoles
www.rsc.org/images/soundbite3-400_tcm18-50620.jpg
Phenethyl isothiocyanate
(R = C6H5CH2CH2–)
isothionates
Both groups have high affinity to
induce Phase II enzyme and
inhibit tumor proliferation.
indoles
www.samispices.com/images/turmericimg.gif
Curcumin from Tumeric
Curcumin is the main biological active compound of
rhizome of tumeric
It has unique ability to fit through aryl hydrocarbon
receptor : estrogen receptor
Curcumin is both strongly anti-inflammatory and
strongly anti-oxidant.
Precaution:
Reduce potency of chemotherapy drugs
accumulate in liver if liberate at high dose
Effect of chemopreventive on carcinogen-metabolizing enzyme
compound
NAD(P)H
Quinone
reductase
CD(μM)
QR induction
IC50 (μM)
Cyp1A
Inhibition
IC50 (μM)
Inhibition of
ODC
induction
IC50 (μM)
Curcumin
2.7
9.7
0.74
3.7
PEITC
0.9
3.2
>5
9.5
Vitamin C
>50
>50
>5
>10
Source: Gerhauser, C and et.al. 2002
Mixing of curcumin with glucosinolate compound
There are many researches indicate that using
the combination of curcumain and glucosinolate
give higher advantage to treat prostate cancer
Using both substances at low dose give good result
Of induce apoptosis and inhibit tumor signaling
We expect that using these two compound in one dose
Will give the same result in HCC
2 mechanisms
Phosphorelate Nrf2 by MAPK
Direct interaction of electrophilic agents with
reactive thiol residues
.
Testing method for this assumption… In vitro…..
Gene-reporter method as high throughput technique
By using Luciferase assay to quantify efficiency
1.
Plasmid construct by using pGL-3 promoter vector consists of
firefly luciferase (luc) gene driven by simian virus 40 (SV40)
2.
This vector was insert with ARE transcriptional enhancer sequence
3. Transfect the vector into cell (primary liver cell & HepG2)
4. Incubate cells with broccoli and curcumin extract and control
substances (zinc and oltipraz), varies time and concentration
5. Lyses cell and measure luciferase activities
Plasmid construction
Premalignant cell prevention
Enhance apoptosis&Inhibit of tumor promoters cascade
Focus on cell survival signaling pathway
ERK, MAPK ,STAT and NfKB are in our focus
Material and method
• Cell line ; same as gene reporter method
• Western blotting
• Testing substances
- mixing of broccoli extract and curcumin
- Test single compound
- Positive control are piroxicam
Expectation……
Getting the effective concentration from in vitro
experiment that can be used further in vivo,
clinical trial and products
The using of combination of curcumin and broccoli
might be the the better alternative way to prevention
Than using single compound.
Zinc was examined in cultured retinal pigment epithelial
cells that it can induce GST enzyme by using
Luciferase method.
(Ha, Khoi-Nguyen., et. al. 2006)
Oltipraz was evaluated as chemopreventive agent
in rat and can inhibit preneoplastic cell in liver
after expose to AFB1.
(Roebuck,B D., et al. 2003)