apoptotic activity of vitamin e phosphate a novel strategy in the cancer chemotherapy l.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
Apoptotic activity of Vitamin E Phosphate: A novel strategy in the cancer chemotherapy PowerPoint Presentation
Download Presentation
Apoptotic activity of Vitamin E Phosphate: A novel strategy in the cancer chemotherapy

Loading in 2 Seconds...

play fullscreen
1 / 33

Apoptotic activity of Vitamin E Phosphate: A novel strategy in the cancer chemotherapy - PowerPoint PPT Presentation


  • 83 Views
  • Uploaded on

Apoptotic activity of Vitamin E Phosphate: A novel strategy in the cancer chemotherapy. Dr. Bashir M. Rezk. Biological activity of VE. Vitamin E derivatives. VE is often supplemented as a chemically stable ester derivative such as Vitamin E Acetate (VEA) Vitamin E Succinate (VES)

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Apoptotic activity of Vitamin E Phosphate: A novel strategy in the cancer chemotherapy' - nimrod


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
apoptotic activity of vitamin e phosphate a novel strategy in the cancer chemotherapy

Apoptotic activity of Vitamin E Phosphate: A novel strategy in the cancer chemotherapy

Dr. Bashir M. Rezk

vitamin e derivatives
Vitamin E derivatives

VE is often supplemented as a chemically stable ester derivative such as

  • Vitamin E Acetate (VEA)
  • Vitamin E Succinate (VES)
  • Vitamin E Phosphate (VEP)
vitamin e derivatives5
Vitamin E derivatives
  • Unlike the redox-active VE , VES, VEA and VEP

are redox-silent

  • Unlike VEA, VES and VEP have side groups that can

be charged at physiological pH

  • Unlike VEA and VE, VES is a potent selective

anticancer agent

the reported rank order of the biological activity of ve and its ester derivatives

Rank order

Assay

Reference

VEA > VE

Rat fetal resorption

Harris & Hudwig

VEA > VE

Rat fetal resorption

Leth & Sondergaard

VEA > VE

Rat fetal resorption

Weiser et al.

VES > VE

Microsomal lipid peroxidation

Carini et al.

Trolox > VE >>> VEA and VES

Lipid peroxidation in cultured endothelial cells

Mabile et al.

VES > VE  VEA

Lipid peroxidation in hepatocytes

Fariss et al.

Trolox > VE > VEA > VES

Microsomal lipid peroxidation

Rezk et al.

The reported rank order of the biological activity of VE and its ester derivatives
apoptotic activity of ves
Apoptotic activity of VES
  • VES induced potent morphological differentiation and growth inhibition in B-16 (1982)
  • VE, VEA, and VEN have no effect
  • VES inhibited growth and caused morphological changes in B-16, NBP2 and C-6 cells (1983)
  • VES enhanced the growth inhibitory effects of ADR on a variety of cancer cells (1986)
  • VES can inhibit the growth of N1E 115 cells (1989)
  • VES induces growth inhibition and apoptogenic activity on a variety of cell lines without affecting the proliferation of normal cells in vitro and in vivo (1990-2004).
mechanism apoptotic activity of ves
Mechanism apoptotic activity of VES
  • Membrane destabilizing activity
  • 1- VES has a detergent like activity
  • 2- Can exist as a deprotonated or protonated
  • 3- 99% of the total VES is charged at neutral pH
  • 4- The uncharged will increase to 25% at pH 6.2
  • 5- The uncharged VES enter cells by p. diffusion
  • 6- The cytotoxic effect of VES increased with acidic pH
  • Dysregulation of signaling pathways
non apoptogenic a and apoptogenic b agents11
Non-apoptogenic (A) and apoptogenic (B) agents
  • Neither trolox succinate nor phytyl succinate caused apoptosis
  • VEG has a very poor apoptogenic activity compared to VES, VEM and VEF
  • VEO has a potent apoptotic activity compared to VES and VEM
  • Flexibility of the terminal carboxyl containing moiety has a role in the apoptotic activity
vitamin e phosphate
Vitamin E Phosphate
  • VEP has been discovered in plant and animal tissues, including human
  • The concentrations of VEP are in general similar to those of VE
  • In rat and pig liver VEP levels were higher
  • In foodstuffs such as chocolate and cheese the concentrations of VEP are 10 to 30 times higher
physiological effect of vep
Physiological effect of VEP
  • Reduced of the intensive rate of metabolism in rabbit muscles
  • Activation of cAMP phosphodiesterase
  • Increasing the rate of phenlalanine hydroxylase
  • Protection against irradiation in rat intestine and cultured mouse skin
  • Increase in sperm survival
  • Improvement of acetylcholine-dependent relaxation in the aged aortic strips exposed to oxidative
  • Protection against LPO in non-heated and heated rat liver microsomes
extraordinary antioxidant activity of vep
Extraordinary antioxidant activity of VEP

Time-course of the effect of VE, Trolox, VEA, VES, & VEP on LPO heated microsomes (A) Induction of hemolysis by VE & VE esters(B)

goal of the study
Goal of the study

The present study has been designed to investigate the effect of VEP on the oesteosarcoma cell line, MG-63, using VES as a reference compound

materials and methods
Materials and Methods
  • Cell Culture
  • Viability assay
  • Proliferation assay (qualitative and quantitative)
  • DNA fragmentation assay for apoptosis
  • Vitamin E determination
  • Membrane fluidity of human erythrocytes
  • Erythrocyte Hemolysis
results discussion 1
Results & Discussion 1
  • VEP induced cell death after 6 h incubation
  • The effect of VEP was superior to that of VES
  • In a conc. of 80 µM both VEP and VES hardly showed any conversion into VE
  • In contrast, VEP showed a massive conversion into VE In cultured mouse skin

Fig. 1. Cytotoxic effect of VES and VEP

on MG-63 cells. The insert shows the

formation of VE from VES and VEP

results discussion 2
Results & Discussion 2
  • The antiproliferative effect of VEP is more potent than that of VES

Fig. 2. Qualitative & Quantative antiproliferative effect of VE, VES and VEP on MG-63 cells

results discussion 3
Results & Discussion 3
  • VEP has a more potent apoptogenic activity (64 ± 11% ) than VES (46 ± 9%)
  • VEP induced a more DNA fragmentation and nucleus condensation

Fig. 3. Apoptotic effect of VE, VES, and VEP on MG-63 cells

induction of apoptosis
Induction of apoptosis

Low concentrations (5-46 µM) had no effect on DNA laddering, whereas high concentrations (46-184) induced significant DNA degradation

Munteanu et al. (Azzi group)

BBRC (2004)

induction of apoptosis23
Induction of apoptosis

VEP, 55.3%

di-VEP, 30.6%

VE, 5%

results discussion 4
Results & Discussion 4
  • Neither trolox succinate nor phytyl succinate caused apoptosis
  • Methylation of the free succinyl carboxyl group (giving VE methyl succinate) completely abolished the apoptogenic activity of VES
  • VEG has a very poor apoptogenic activity compared to that of VES, VEM and VEF
  • Apoptogenic potency also differs between vitamin E oxalate (VEO), vitamin E malonate (VEM) and VES.
  • The apoptogenic activity correlates with the flexibility of the terminal carboxyl containing moiety
  • Fewer than four carbon atoms in the terminal dicarboxylic moiety were necessary for the potent apoptogenic activity
results discussion 6
Results & Discussion 6
  • Four carbon atoms or more in the terminal carboxyl moiety are implicated in the flexibility of the ester derivatives
  • More flexibility, less apoptotic activity

Vitamie E pimelate

structural requirements
Structural requirements
  • Domain I is considered as functional domain
  • Domain II is regarded as signalling domain
  • Domain III is an orientation domain

Fig. 4. Structures of VES and VEP showing major domains

results discussion 7
Results & Discussion 7
  • Both VES and VEP decreased membrane fluidity of erythrocytes
  • VE has no significant effect

Fig. 6. Effect of VE, VES, and VEP on membrane fluidity of erythrocytes

results discussion 8
Results & Discussion 8
  • The cytotoxicity of VEP on erythrocytes is higher at acidic pH

Fig. 6. Induction of hemolysis of erythrocytes by VEP

membrane destabilizing activity of ves or vep
Membrane destabilizing activity of VES or VEP
  • 1- VES has a detergent like activity
  • 2- Can exist as a deprotonated or protonated
  • 3- 99% of the total VES is charged at neutral pH
  • 4- The uncharged will increase to 25% at pH 6.2
  • 5- The uncharged VES enter cells by p. diffusion
  • 6- The cytotoxic effect of VES increased with acidic pH
  • Possibly protonation of the phosphate group is involved in the cytotoxic effect of VEP
conclusion
Conclusion
  • VEP induces cell death, prevents cell proliferation and provokes apoptosis in MG-63
  • This is probably due to a membrane destabilising activity by acting as a detergent
  • The apoptogenic activity requires the combination of the three structural domains, i.e. functional, signalling and orientation domains
plans of the pharmacology unit
Plans of the Pharmacology Unit
  • The ICGEB project on vitamin E succinate
  • The PhD program on vitamin E succinate
  • The PhD program on vitamin E phosphate
  • Collaboration with a Japanese group on vitamin E oxalate

Dr. Bashir M. Rezk, Dr. Hafez F. Hafez, Prof. dr. Mohamed M. El-Khayal and Prof. dr. Mahmoud M. El-Merzabani