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The Roles of Tocotrienols in Chemo-prevention of Degenerative Diseases

-Tocopherol is a popular scientific research subject for the past half a century, hoping that this powerful antioxidant can plays its chemo-preventive roles against degenerative diseases, benefiting the mankind.  However, the research outcomes are far from satisfactory and even disappointing.  Miller III et al. of Johns Hopkins Medical Institute, USA [1] and Bjelakovic et al. of Copenhagen University Hospital, Denmark [2] carried out reviews and meta-analyses on previous clinical trials involving -tocopherol and conclude that -tocopherol increases the all-cause mortality.  This unexpected outcome caught many consumers in dilemma, to stop or continue -tocopherol supplementation.

Current clinical knowledge indicates that tocotrienols have excellent potential for chemo-prevention of degenerative diseases.  We shall analyze the roles of tocotrienols in chemo-prevention of degenerative diseases, especially in the chemoprevention of cancers and cardiovascular diseases, and neuroprotection.

Chemoprevention of Cancers

Currently, there is only one clinical trial outcome on breast cancer with tocotrienols [3].  240 subjects with stage 1 or stage 2 breast cancer were selected for the five years clinical trial.  The subjects were evenly divided into two groups, a group took placebo with Tamoxifen whereas the other group took palm tocotrienol-rich fraction with Tamoxifen.  The outcome of the clinical trial is that tocotrienols prolong the lives of breast cancer patients and inhibit the recurrence of breast cancer. 

The rest of scientific evidence on chemo-prevention of breast cancer is obtained from in vitro and animal model studies [4-26].

Table 1 summarises the required dosages of tocotrienols in inhibiting proliferation and inducing apoptosis for human breast cancer cells culture [4,5].  Table 1 reveals:

  • Tocotrienols are excellent in inhibiting proliferation and inducing apoptosis of breast cancer cells whereas -tocopherol is clearly ineffective.

  • The dosage needed for inhibiting proliferation is less than that for inducing apoptosis.

  • Tocotrienols have synergistic effect with Tamoxifen for inhibiting proliferation of both estrogen receptor positive and negative breast cancer cells.

  • The potency of tocotrienol-rich fraction with high -tocopherol content is far from satisfactory as compared with equivalent tocotrienol mixtures without -tocopherol, revealing the antagonistic effect of -tocopherol on inhibition of proliferation and inducing apoptosis potency of tocotrienols.

Table 1Inhibitory effects on human breast cancer cells

 

Tamoxifen

-T

-T3

-T3

-T3

v

TRF

 Inhibition of proliferation, IC50:

 MCF-7

 MCF-7#

 MDA-MB-435

 MDA-MB-435#

 ZR-75-1

 ZR-75-1*

 

0.11

 

242

 

290

 109

>2320

>23

>23

 

14

0.2

212

3.5

18

5

 

4.9

0.02

73

4.6

10

6

 

5.0

0.008

227

15

9

9

 

8.3

0.08

156

6.3

12.7

6.3

 

9.8

1.2

439

9.5

13

13

 Inducing apoptosis, EC50:

 MCF-7

 MDA-MB-435

 

 

>464

>464

 

33

414

 

36

68

 

18

33

 

 

-T: -tocopherol;  -T3: -tocotrienol; -T3: - tocotrienol; -T3: - tocotrienol;

TRF: tocotrienol-rich fractioncontaining 32% -T, 25% -T3, 29% -T3 & 14% -T3.

vcalculated weighted average IC50 for tocotrienol mixture equivalent to the composition of TRF.  IC50half maximal inhibitory concentration˙EC50half maximal effective concentration.  # in the presence of  Tamoxifen. * in the presence of  10-8 M estradiol.  All units are in M/L.

  

Table 2Inhibitory effects on mouse mammary epithelial cells

 

-T

-T

-T

 

 

 Inhibition of proliferation, IC50:    CL-S1

                                                 -SA

                                                 +SA

>120

>120

>120

>120

>120

>120

55

47

23

 

 

 Inducing apoptosis, LD50:     CL-S1

                                          -SA

                                          +SA

>250

>250

>250

>250

>250

>250

>250

166

126

 

 

 

-T3

-T3

-T3

v

TRF

 Inhibition of proliferation, IC50:     CL-S1

                                                  -SA

                                                  +SA

12

7

5

8

5

4

7

4

3

9

5

4

13

7

6

 Inducing apoptosis, LD50:     CL-S1

                                          -SA

                                          +SA

27

28

23

19

17

14

16

15

12

20

19

16

50

43

38

-T: - tocopherol;  -T: - tocopherol;  -T: - tocopherol;  -T3: - tocotrienol; -T3: - tocotrienol; -T3: - tocotrienol; TRF: tocotrienol-rich fractioncontaining 20.2% -T, 16.8% -T3, 44.9% -T3 & 14.8% -T3 vcalculated weighted average IC50 for tocotrienol mixture equivalent to the composition of TRF calculated weighted average IC50 for tocotrienol mixture equivalent to the composition of TRF.  IC50 half maximal inhibitory concentration˙LD50 Median Lethal Dose. All units are in M/L.

Table 2 summarises the required dosages of tocotrienols in inhibiting proliferation and inducing apoptosis of mouse mammary epithelial cells in vitro [6,7].  Table 2 reveals:

  • The required dosages of tocotrienols to inhibit proliferation and induce apoptosis are lower (lower IC50/EC50/LD50 means higher potency) than tocopherols.  汛-Tocopherol has very weak potency and other tocopherols are ineffective.

  • For both inhibition of proliferation and inducing apoptosis, the order of potency is 汛-tocotrienol > 汕-tocotrienol > 污-tocotrienol > 汐-tocotrienol.

  • Inhibiting proliferation needs lower tocotrienol dosages than inducing apoptosis.

  • The potency of tocotrienol-rich fraction with high 汐-tocopherol content is far from satisfactory as compared with equivalent tocotrienol mixtures without 汐-tocopherol, revealing the antagonistic effect of 汐-tocopherol on inhibition of proliferation and inducing apoptosis potency of tocotrienols.

  • CL-S1, -SA and +SA are pre-neoplastic, neoplastic and maglignant stages of mouse mammary epithelial cellthe sensitivity of inhibitory effect for tocotrienols increases with the degree of tumor progression. 

Besides breast cancer, scientific reports on tocotrienols in chemo-prevention of other cancers like prostate [27, 28], lung [29], liver [30-34]. Skin [35] and colorectal [36] are available. Although the information is rather limited, they reveal that tocotrienols have excellent potential in chemoprevention.

Table 3: Comparison of anti-angiogenic, inhibition of DNA polymerase 竹   and telomerase activities of various vitamin E

tocopherols

-T

-T

-T

-T

Anti-angiogenesis:

   Inhibition of formation of tube, IC50

   Inhibition of proliferation, IC50

 

> 200

> 200

 

> 200

> 200

 

> 200

> 200

 

> 200

> 200

Inhibition of DNA polymerase activity, IC50

> 200

> 200

> 200

> 200

Inhibition of telomerase activity

nil

nil

nil

nil

tocotrienols

-T3

-T3

-T3

-T3

Anti-angiogenesis:

   Inhibition of formation of tube, IC50

   Inhibition of proliferation, IC50

     

9.3

38.0

 

3.2

6.3

 

5.9

11.2

 

2.4

5.1

Inhibition of DNA polymerase activity, IC50

80.6

27.5

38.7

18.4

Inhibition of telomerase activity

+

+++

++

++++

-T: - tocopherol; -T: -tocopherol;  -T: - tocopherol;  -T: - tocopherol;  -T3: - tocotrienol; -T3: -tocotrienol;  -T3: - tocotrienol; -T3: - tocotrienol; IC50 half maximal inhibitory concentration. All units are in M/L.

Recently, researchers at Tohoku University, Japan discover that tocotrienols have anti-angiogenic, inhibition of DNA polymerase 竹 and inhibition of telomerase activities (Table 3) [36-42].  Without formation of new blood vessels, there is no supply to blood and nutrients to the cancer cells, consequently the cancer cells are unable to grow and undergo metastasis, leading to apoptosis and death.  Telomerase enable indefinite cancer cell division and ever growing.  Tocotrienols inhibit telomerase activity and therefore should also able to inhibit tumor growth.  Table 3 reconfirms that the order of anti-cancer potency is -tocotrienol > -tocotrienol > -tocotrienol > -tocotrienol and tocopherols are ineffective.  Tocotrienols also inhibit carcinogens in inducing tumor formation [8, 43-45] and have other chemopreventive mechanisms for cancers [46-52]. 

Chemo-prevention of Cardiovascular Diseases

***50 subjects with carotid artery atherosclerosis were selected for the four years clinical trial [53-55].  The subjects were evenly divided into two groups, a group took placebo whereas the other group took tocotrienol-rich fraction.  Change in carotid stenosis was measured with bilateral duplex carotid ultrasonography.  After four years of tocotrienol-rich fraction supplementation, 40% of the patients has regression in carotid stenosis whereas only 12% of the patients has progression of carotid stenosis.  On the other hand, 60% of the placebo group has progression in carotid stenosis and only 8% has regression in carotid stenosis (Table 4).  

Table 4: Changes in carotid stenosis after 6, 24, 36 and 48 months TRF supplementation

 

Marked regression

 
Regression

No
change

 
Progression

Marked progression

6 monthsPlacebo
                TRF

0
1

0
5

20
18

5
1

0
0

24 monthsPlacebo
                  TRF

0
1

0
7

14
15

7
2

4
0

36 monthsPlacebo
                  TRF

0
1

0
7

13
15

8
2

4
0

48 monthsPlacebo
                  TRF

0
2

2
8

8
1
2

11
3

4
0

         TRF: tocotrienol-rich fraction; units: number of subject (patient) 

Other in vitro experiments indicate that tocotrienols can reduce monocyte-endothelial cell adhesion and prevent atherosclerosis [56-58]. 

The outcomes of tocotrienols clinical trials on cholesterol lowering are inconsistent.  Some researchers reported that tocotrienols are effective in lowering cholesterol via post transcriptional suppression of 3-hydroxy-3-methylglutaryl coenzuyme A (HMG-coA) reductase and hence reducing cardiovascular diseases risks [59-63] whereas others reported that tocotrienols have no effect of serum lipid profiles [64-66].  Improper clinical trial design is the likely cause of the controversy.  -Tocopherol, squalene and phytosterols are confounding agents and can affect cholesterol levels in the blood and these were not properly controlled in those clinical trials.  

Tocotrienols have cholesterol lowering [67-79], hypotension [80,81], anti-inflammatory [47-49], anti-platelet aggregation and anti-thrombotic effects [82] based on in vitro and animal model studies.  Inflammation is the root cause of cancers, cardiovascular diseases and other diseases whereas platelet aggregation and thrombus formation trigger cardiovascular diseases and stroke. 

Both -tocotrienol and its metabolite -carboxylethyl-6-hydroxychroman (-CEHC) are natriuretic [81], stimulate sodium secretion in vivo, inhibiting high blood pressure and other cardiovascular diseases due to high salt intake.

 

Neuroprotection

Glutamate is a neurotransmitter needed for normal intercellular communication.  During ischemia (a deficiency in blood flow) or hypoxia (a deficiency in oxygen) such as in the case of an embolic stroke, there is a sudden release of extracellular glutamate. Excessive exposure to glutamate can kill neuronal cells, causing mortality or morbidity. 

Sen et al. of Ohio States University, USA discover that tocotrienols at nanomolar concentration can fully protect the neuronal cells from glutamate-induced toxicity [83-89].  This has tremendous impact in prevention of mortality and morbidity due to embolic stroke.  This research was supported by the National Institute of Health, USA and received over a million dollars of research funding.  Unlike chemoprevention of other degenerative diseases, -tocotrienol has the highest potency in neuroprotection.  The Japanese researchers concur with Sen et al. that -tocotrienol has the highest potency in neuroprotection [90, 91].

 

Bioavailability 

The bioavailability of tocotrienols must be sufficient at the respective organs or tissues, in order to be effective in chemo-prevention of degenerative diseases.  The bioavailability of tocopherols and tocotrienols are at least partly dependent on the relative binding affinity with 汐-tocopherol transfer protein (汐-TTP) [92-94].  Tocotrienols require fats for absorption.  The bioavailability of tocotrienols is significantly higher under fed conditions when compared with fasted conditions [95,96].  Therefore we intentionally retain the natural food emulsifiers: monoacylglycerols and diacylglycerols during our manufacturing process in order to increase the bioavailability of the tocotrienol-rich fraction.  Tocotrienol-rich fraction produced by other manufacturers does not contain natural food emulsifiers as these have been destroyed during their destructive processing (transesterification). 

Conclusion

Tocotrienols play an important role in chemo-prevention of degenerative diseases.  The bioavailability of tocotrienols must be sufficient in order to have effective chemo-prevention of degenerative diseases.  Effective multiple chemo-preventive functionality and without any known adverse side effect shall enable tocotrienol-rich fraction with reduced -tocopherol content to benefit the well-being of mankind.

References

 

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Reviews and other references

Gee P T (2005).   Misconceptions and the need to re-look at clinical trials for vitamin E. Malaysian Oil Science and Technology, 14(1): 17-25.

Gee P T and Goh S H (2006).   Functional minor constituents in oils and fats: Update 2006. Malaysian Oil Science and Technology, 15(1): 8-14.

Gee P T (2007a).  Challenges in commercialisation of tocotrienol projects. Malaysian Oil Science and Technology, in press.

Gee P T (2007b). Processes and their impact on the quality of palm tocotrienols. In Proceedings of Chemistry & Technology Conference, International Palm Oil Congress (PIPOC) 2007, 26-30 August 2007, Kuala Lumpur (Malaysia), Pp 84-91.

Gee P T (2007c). Uniqueness of palm oil.  Presented at Oils and Fats International (OFI) China 2007 Conference, 11-13 September 2007, Guangzhou (China).

Schaffer S, M邦ller W E and Eckert G P (2005).  Tocotrienols: Constitutional effects in aging and disease.  J. Nutr. 135(2): 151-154.

Sen C K, Khanna S and S. Roy S (2006), Tocotrienols: vitamin E beyond tocopherols, Life Sci. 78(18): 2088每2098.

Sen C K, Khanna S and Roy S (2007).  Tocotrienols in health and disease: the other half of the natural vitamin E family.  Molecular Aspects of Medicine, in press. doi: 10.1016/j.mam.2007.03.001.  

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