TEST BANK For Porth's Essentials of Pathophysiology, 5th Edition by Tommie L ...
Curcumin_NF-KB
1. Chemo preventive and
therapeutic effects of
Curcumin
Duvoix et al.
Cancer Letters 223 (2005) 181–190
Presented by: Mahshid Moballegh Nasery
MSc student of medical toxicology
1
2. plant extracts subdivided as chemo
preventive agents
Plant extractsChemopreventive agents
Blocking agents
Suppressing agents
Presented by: Mahshid Moballegh Nasery
low side effects and toxicity
2
3. Schematic representation of multistep-
carcinogenesis
Ref:duvoix et al.(from Surh et al. with modifications)
Presented by: Mahshid Moballegh Nasery 3
4. Molecular structure of selected
chemopreventive agents
Ref:duvoix et al.
Presented by: Mahshid Moballegh Nasery 4
5. curcumin
Curcuma longa L.Ref: Duvoix et al. better in wiki pedia
Is one of the best characterized
chemopreventive agents
Anti-oxidative
Anti-inflammatory
Anti-septic
Properties
Used in
Presented by: Mahshid Moballegh Nasery
Indian medicine
Culinary traditions
As a drug or as an
adjuvant in cancer therapy
5
6. Anti-carcinogenic activities of curcumin
• Benz(a)pyren,
• Phorbol esters
Inhibits cancer development in rat stomach
Tumour formation and promotion
Presented by: Mahshid Moballegh Nasery 6
7. Anti-carcinogenic activities of curcumin
Curcumin is a goodanti-angiogenesis agent can Inhibition of :
• Vascular endothelial growth factor (VEGF)
• Angiopoietin1 and 2
In EAT cells,
o VEGF
o Angiopoietin 1
In NIH 3T3 cells
Tyrosine kinase Flk-1/KDR (VEGF receptor-2) In HUVEC cells
Presented by: Mahshid Moballegh Nasery 7
8. Anti-carcinogenic activities of curcumin
• Human telomerase reverse transcriptase (hTERT) expression
• Reducing telomerase activity
• Potentialized in the presence of oestrogen in breast cancer cells
• It allows sensitising ovarian cancer cells to cisplatin enhancing
chemotherapeutic treatment
In MCF-7 cells
Displays an inhibiting effect on:
Anticancer effect :
Presented by: Mahshid Moballegh Nasery 8
9. Contribution of curcumin to the induction
of apoptotic mechanisms
Ref:duvoix et al 2005
• Induce apoptosis in:
HL-60
K562
MCF-7
HeLa
• leads to apoptosis in :
scleroderma lung
fibroblasts (SLF) without
affecting normal lung
fibroblasts (NLF)
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10. Anti-inflammatory effects of curcumin
Inhibition of:
Cyclooxygenase 2 (COX-2)
lipoxygenase (LOX),
Protection :
Keratinocytes
Fibroblasts
Reduction of: Oxidative and inflammatory stress in Alzheimer patients
Effect on galactose-induced cataractPancreatitis improves
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against H2O2-induced damages
12. Anti-inflammatory effects of curcumin
Curcumin abolishes:
NF-kB binding to the DNA
IKK activation
IkBa phosphorylation
Activation of NF-kB
lead to Diseases such as the
Pathogenesis of alcoholic liver disease
Ref:tgrbio.com
Presented by: Mahshid Moballegh Nasery 12
13. Anti-inflammatory effects of curcumin
Inhibits JNK activation at (MAPKKK )
TPA c-Jun & c-Fos activation *
TPA_induced PKC in NIH 3T3 mouse fibroblast cells
modifies AP-1 dimer compositionCurcumin
JAK 2
Tyrosine kinase 2
STAT3
STAT4
Blocking by Curcumin
Inhibits IL-12 activation
13Presented by: Mahshid Moballegh Nasery
14. Inhibition of nuclear factor kappa B and
activating protein-1 transcription factors
Curcumin is an activator of heme-oxygenase (HO)-1 in kidney epithelium cells
Involving the NF-kB pathway
Curcumin Superoxide radical levels
Decrease
Acts on the amount of free radical
14Presented by: Mahshid Moballegh Nasery
15. Inhibition of nuclear factor kappa B and
activating protein-1 transcription factors
Aflatoxine-DNA adduct formation
Ethoxyresorufin
Methoxyresorufin
Pentoxyresorufin
Carcinogen activation induced by CYP 1A1
15Presented by: Mahshid Moballegh Nasery
16. Inhibition of nuclear factor kappa B and
activating protein-1 transcription factors
liver and kidney
Inhibites GST
K562 and Jurkat leukemia cells
NF-kB and AP-1 signalling pathwaysCurcumin
Reduces GSTP1-1 expression
Concentration-dependent effects:
Activity of GST and quinone reductase
In human melanoma cells
16Presented by: Mahshid Moballegh Nasery
17. Conclusions
curcumin as a cancer therapeutic agent
curcumin leads to a strong modification of cell
signalling pathways reduction :
NF-kB transcription factors
AP-1 transcription factors
Ref: www.siliconvalleyfit
Presented by: Mahshid Moballegh Nasery 17
Chemoprevention:use of natural or synthetic chemicals allowing suppression, retardation or inversion of carcinogenesis
Chemopreventive products present low side effects and toxicity
Most chemopreventive agents known until today are plant extracts subdivided into two classes:
1-blocking agents, which inhibit the initiation step by preventing carcinogen activation
2-suppressing agents, which inhibit malignant cell proliferation during promotion and progression steps of carcinogenesis
Pro carcinogen under metabulic activation can be a carcinogen
When a carcinogen exposure to a normal cell normal cell can altered an initial cell
Here are some of chemopreventive agent that found in natural compound:
kahweol and cafesteol=>two diterpens present in coffee=>were shown to protect cells against mutagenesis and carcinogenesis in animal models
diallyl sulphide=>that are compound from garlic=>which blocks carcinogenesis in mice=>because of their allyl groups
Emodin=> from Cassia siamea(گیاه سنا)=>anti-tumoral effects on skin tumour in mice
Lycopene:extracted from tomatoes =>blocks dimethyl benzanthracene induced carcinomas in hamster
curcumin and resveratrol:A distinct class of chemopreventive agents including curcumin and resveratrol
this review summarize one of the best characterized chemopreventive agents, curcumin or diferuloylmethane extracted from the root of Curcuma longa(زرچوبه)
Curcumin presents strong anti-oxidative, anti-inflammatory and anti-septic properties and is widely used in Indian medicine and culinary traditions
Many data give additional evidence that curcumin could also serve in cancer therapy as a drug or as an adjuvant to traditional chemotherapy.
This review will focus on both chemopreventive and chemotherapeutic effects of curcumin.
There are evidence that curcumin contributes to the inhibition of tumour formation and
promotion as cancer
initiation, promotion or progression of tumours is decreased or blocked by this compound
بعد از روی اسلاید
curcumin was described as a good anti-angiogenesis agent explaining its chemopreventive effect at the level of tumour promotion
This phenomenon could be explained by:اسم دوتا فاکتور رو بگو
3T3سلول فیبرو بلاست
HUVEC: Human umbilical vein endothelial cellsبرای مطالعه سلول های اندوتلیال
Kdr رسپتور تیروزین کیناز نوع 3
Flk:Fetal Liver Kinaseهمون )kdr(
هر دو گیرنده vegf
VEGFرگزایی رو تحریک میکنه
Angio protein:احتمالا آنزیم پروتیولیتیک
Curcumin also displays an inhibiting effect on human telomerase reverse transcriptase (hTERT) expression
Anticancer effect of curcumin seems to be potentialized in the presence of oestrogen in breast cancer cells and it inhibits genes which are under the
influence of the oestrogen receptor
it allows sensitising ovarian cancer cells to cisplatin, enhancing chemotherapeutic treatment
Curcumin can induce apoptosis in cancer cells without cytotoxic effects on healthy cells
Curcumin can induce apoptosis in various cell lines including HL-60, K562, MCF-7 and HeLa
Curcumin also leads to apoptosis in scleroderma lung fibroblasts (SLF) without affecting normal lung fibroblasts (NLF)
This effect seems to be due to the weak level of protein kinase (PK) C3 in SLF, generating low levels of glutathione S-transferase (GST)
There are many disease have been studied but the important point is:
Unfortunately, in selected pathologies, curcumin is able to inhibit chemotherapeutic effects by reducing some drugs for example:
Doxorubicin induced apoptosis in breast cancer cells.
Curcumin exhibited anti-oxidant properties and inhibited both JNK activation and mitochondrial release of cytochrome c in a concentration-dependent manner.
association of curcumin with other anticancer drugs should be carefully evaluated in breast cancer.
Even should be considered a limitation of exposure of patients to curcumin-containing foods
اول از خود اسلاید بگو
curcumin protects keratinocytes and fibroblasts against H2O2-induced damages
Pancreatitis improves after curcumin treatment, which blocks key inflammatory signals
اول قسمت سبز
in K562 leukemia cells in which curcumin strongly inhibits tumor necrosis factor (TNF) -induced NF-kB and TPA-induced AP-1 binding to the corresponding target sequences on GSTP1-1 gene promoter or consensus binding sites
فاکتور های بغلی که میتونن با کورکومین مهار شن
This inhibiting effect should be considered to improve chemotherapeutic treatment as most anticancer drugs, including doxorubicin induce NF-kB leading to the development of drug resistance
اول انگلیسی سمت چپ
توضیح شکل :
NF-kb can attache to ikbα and make complex then ikk kinase activate and we have ikbα phosphorilation
After phosphorilation NF-kb can be seprate and be activated.
NF-kB inhibition by curcumin is certainly an interesting strategy against diseases such as the pathogenesis of alcoholic liver disease, in which NF-kB is
activated
demonstrated that curcumin inhibits the signal transduction pathway that couse of JNK activation at mitogen-activated protein kinase kinase kinase (MAPKKK)
Curcumin also inhibits TPA -induced c-Jun and c-Fos activation by acting at the PKC level in a non-competitive way demonstrated that curcumin modifies AP-1 dimer composition
Furthermore, TPA-induced PKC is abolished by curcumin in NIH 3T3 mouse fibroblast cells
Curcumin was described to act on the Janus Kinase-Signal Transducer and Activator (JAK/STAT) pathway.
Curcumin inhibits IL-12 activation by blocking JAK 2, tyrosine kinase 2, STAT3 and STAT4, in experimental allergic encephalomyelitis, a model of multiple sclerosis
curcumin is an activator of heme-oxygenase (HO)-1 through the activation of Nrf2/anti-oxidant response element pathway in kidney epithelium cells
In kidney cells, inhibition of IkBa phosphorylation decreases HO-1 induction by curcumin thus involving the NF-kB pathway
Curcumin also directly acts on the amount of free radical within the cell by decreasing superoxide radical levels
curcumin inhibits alkylation reaction ofاتوکسی رزورفین, متوکسی رزورفین and پنتوکسی رزورفین catalysed by CYP 1A1, 1A2 and 2B1 in rat liver
Similarly, aflatoxine-DNA adduct formation, catalysed by the CYP system, is inhibited by curcumin
Adductمحصول افزایشی
In DMBA(دای متیل بوتیل آمین)-treated MCF7 cells, CYP activity is dramatically reduced by curcumin
illustrated that curcumin activates the AhR while inhibiting carcinogen activation induced by CYP 1A1 in both oral SCC cells and intact oral mucosa
curcumin significantly reduces GSTP1-1 expression in K562 and Jurkat leukemia cells by inhibiting NF-kB and AP-1 signalling pathways
Effect of curcumin seems to be concentration-dependent and, if curcumin activates GST at low doses, high concentrations inhibit GST activity in rat
curcumin induces the activity of phase II drug metabolizing enzymes in male mice, particularly GST and quinone reductase in liver and kidney
curcumin is a strong GST inhibitor in human melanoma cells in which GSTP1-1 is the major isoform
