-Tocopheryl Succinate, the Most Effective Form of Vitamin ...

Review
-Tocopheryl Succinate, the Most Effective Form of
Vitamin E for Adjuvant Cancer Treatment: A Review
Kedar N. Prasad, PhD, Bipin Kumar, MD, Xiang-Dong Yan, MD, Amy J. Hanson, MS, William C. Cole, PhD
Center for Vitamins and Cancer Research, Department of Radiology, University of Colorado Health Sciences Center, Denver,
Colorado
Key words:
-tocopheryl succinate, cancer, gene expressions, differentiation, growth inhibition, apoptosis
In 1982, it was established that alpha-tocopheryl succinate ( -TS) was the most effective form of vitamin E
in comparison to
-tocopherol,
-tocopheryl acetate and
-tocopheryl nicotinate in inducing differentiation,
inhibition of proliferation and apoptosis in cancer cells, depending upon its concentration. During the last two
decades, several studies have confirmed this observation in rodent and human cancer cells in culture and in vivo
(animal model). The most exciting aspect of this
-TS effect is that it does not affect the proliferation of most
normal cells. In spite of several studies published on the anti-cancer properties of
-TS, the value of this form
of vitamin E has not drawn significant attention from researchers and clinicians. Therefore, a critical review on the
potential role of -TS in the management of cancer is needed. In addition, such a review can also provide in-depth
analysis of existing literature on this subject. -TS treatment causes extensive alterations in gene expression; however,
only some can be attributed to differentiation, inhibition of proliferation and apoptosis.
-TS also enhances the
growth-inhibitory effect of ionizing radiation, hyperthermia, some chemotherapeutic agents and biological response
modifiers on tumor cells, while protecting normal cells against some of their adverse effects. Thus, -TS alone or in
combination with dietary micronutrients can be useful as an adjunct to standard cancer therapy by increasing tumor
response and possibly decreasing some of the toxicities to normal cells.
Key teaching points:
•
-TS is the most effective form of vitamin E in comparison to
-tocopherol,
-tocopheryl acetate and
-tocopheryl nicotinate in
inducing differentiation, inhibition of proliferation and apoptosis in cancer cells without affecting the proliferation of most normal
cells.
•
-TS treatment causes extensive alterations in gene expression in tumor cells; however, only some can be attributed to
differentiation, inhibition of proliferation and apoptosis. Not only is the effect of -TS on inhibition of proliferation in cancer cells
independent of antioxidant action, but the well-established antioxidants,
-tocopherol and butylated hydroxyanisole (having
antioxidant activity similar to
-tocopherol but without vitamin E action), also may inhibit proliferation of cancer cells by
mechanisms that are independent of their antioxidation activity.
•
-TS enhances the growth-inhibitory effects of ionizing radiation, chemotherapeutic agents, hyperthermia and some biological
response modifiers on cancer cells, but not on normal cells.
•
-TS, together with dietary micronutrients, can be used as an adjunct to standard and experimental cancer therapies in order to
improve their efficacy.
INTRODUCTION
The name tocopherol for vitamin E was derived from the Greek
term meaning “to bear offspring”, because it was first recog-
Although vitamin E was first recognized in 1922 [1], its
nized to be essential for reproduction in rats. Among various
isolation was not achieved until 1936 [2]. Subsequently, the
forms of -tocopherol ( -T), , ,
and
forms are important.
structural formula of vitamin E was found to be C H O [3],
-tocopherol is considered the most biologically active form of
29
50
2
and soon afterwards, its chemical synthesis was accomplished.
vitamin E,
-tocopherol possesses 25% to 40% of the activity
Address reprint requests to: Kedar N. Prasad, Ph.D., Campus Box C-278, UCHSC, 4200 E. 9th Ave. Denver, CO 80262. E-mail: Kedar.Prasad@UCHSC.edu
This study was supported by Shafroth Memorial Fund.
Journal of the American College of Nutrition, Vol. 22, No. 2, 108–117 (2003)
Published by the American College of Nutrition
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-Tocopheryl Succinate and Cancer
of -T, while -tocopherol has only 20% of the activity of -T.
carcinogenic mechanism or a novel anti-cancer agent in order
Esterified forms of vitamin E such as
-tocopheryl acetate
to acquaint researchers with the methods or events that led to
( -TA), -tocopheryl nicotinate ( -TN) and -tocopheryl suc-
such a discovery. In 1979, we demonstrated, for the first time,
cinate ( -TS) are also commercially available.
that aquasol vitamin E (dl- -TA, USV laboratories, Tucoma,
Although a few reviews have focused on vitamin E and
N.Y.) induced morphological differentiation and enhanced the
cancer prevention [4 – 6], the role of vitamin E in cancer treat-
effect of x-irradiation on murine neuroblastoma (NB) cells in
ment has not received adequate attention. This may have been
culture [56] and certain chemotherapeutic agents on NB and rat
due to the fact that the most widely used forms of vitamin E
glioma cells [57]. Subsequently, it was found that the solvent
( -T and
-TA dissolved in ethanol) exhibited no anti-cancer
for aquasol vitamin E by itself was toxic to melanoma cells,
activity on tumor cells in culture or in vivo. Since the discovery
suggesting that part of vitamin E’s effect could have been due
of -TS as the most effective form of vitamin E in comparison
to its solvent [7]. The solvent was considered a trade secret;
to the water soluble preparation of
-T, and
-TA or ethanol
therefore, the solvent composition was never revealed. In order
soluble
-T,
-TA and
-TN for inducing differentiation, in-
to avoid the inherent difficulty of using an aqueous form of
hibition of cell proliferation and cell death in murine melanoma
vitamin E,
-T and
-TA obtained in oil were dissolved in
cells in culture [7], several publications have shown that
-TS
ethanol. Both forms of vitamin E in this solvent were found to
produces similar effects on a variety of human and rodent
be inactive in melanoma cells in culture [7]. This led to the use
tumor cell lines without affecting the proliferation of most
of two other esters of vitamin E, -TN and -TS. These forms
normal cells in vitro [8 –37] and in vivo [10,19,20,38 – 41].
of the vitamin E were never tested in any experimental systems.
Results of several studies have revealed that -TS affects these
In 1982, we reported that
-TS induced morphological and
biological processes by altering expression of those genes that
biochemical differentiation, inhibition of proliferation and cell
are involved in differentiation, regulation of proliferation and
death in murine melanoma (B16) cells in culture, depending
apoptosis [13–15,17–19,23,31,34 –37,42– 48]. In addition, the
upon the concentration of -TS (Fig. 1). It is interesting to note
role of -TS in modifying the effects of radiation [49], chemo-
that the dose range of
-TS between growth inhibition and
therapeutic agents [11,21,22], hyperthermia [50,51] and bio-
lethality is very narrow. A concentration of about 5
g/mL (9.4
logical response modifiers [17,20,52–54] on tumor and normal
M) of -TS caused about 50% growth inhibition without any
cells has also been investigated. Recently, Kline et al. [34] and
significant cell death, whereas a concentration of 10
g/mL
Neuzil et al. [55] have reviewed anti-cancer activity of
-TS
(18.8
M) caused almost 100% lethality. When the effect of
and its potential mechanisms. It has been suggested that
-TS
aqueous preparations of vitamin E was compared with -TS, it
exhibits dual functions: anti-cancer activity when present as
-TS and anti-inflammatory effect when converted to -T [55];
however, Weber et al. [20] have reported that
-T exhibits a
weak anti-cancer activity in vivo in comparison to -TS. These
reviews did not include studies on the interaction between -TS
and standard and experimental cancer therapeutic agents. Fur-
thermore, in view of the fact that
-TS may be more useful in
cancer treatment when employed in combination with current
therapeutic modalities than by itself, a detailed critical review
on
-TS and cancer treatment would be helpful.
This review provides the following: (a) a brief description of
the historical perspective of the discovery of -TS as an effective
anti-cancer agent in inducing differentiation, inhibition of prolif-
Fig. 1. Effect of various forms of tocopherol (vitamin E) on the growth
eration and apoptosis; (b) changes in expressions of genes and
of mouse melanoma (B-16) cells in culture. Cells (105) were plated in
their products, and their translocation after -TS treatment, and (c)
Lux tissue culture dishes (60 mm). Twenty-four hours after plating,
the interaction of
-TS with commonly used tumor therapeutic
D- -tocopherol acid succinate (Sigma; soluble in ethanol), DL- -
agents and some biological response modifiers on cancer cells and
tocopherol free alcohol (Hoffmann-La Roche; soluble in specialized
normal cells, and their potential mechanisms of action.
solvent) and Aquasol DL- -tocopherol acetate (USV Laboratories;
soluble in specialized solvent) at various concentrations were added
individually to separate dishes. Growth medium and drug were changed
at two days after treatment, and the growth inhibition, based on the
HISTORICAL PERSPECTIVE OF
amount of protein per dish, in the treated culture was determined at
THE DISCOVERY OF
-TS AS AN
three days after treatment. The average value of the untreated controls
ANTI-CANCER AGENT
was considered 100%, and the growth inhibition of treated cultures was
expressed as percentage of untreated controls. The amount of protein
It is essential that a review provides a brief description of
per dish in the untreated cultures was 850
67
g. Each point on the
the scientific processes leading to the discovery of a new
curve represents an average of nine samples; bars, S.D. [7].
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-Tocopheryl Succinate and Cancer
was found that
-TS was more effective than
-T or
-TA in
and enhanced the growth-inhibitory effect of adriamycin on these
reducing the growth of murine melanoma cells in culture (Fig.
cells [11]. Two papers that were relevant to cancer prevention
2). Thus, -T and -TA in water soluble preparations exhibit a
were published independently by Radner and Kennedy [60] and
weak anti-cancer activity in vitro, whereas ethanol soluble -T
Borek et al. [61]. They showed that
-TS treatment was most
and
-TA were inactive.
effective in reducing radiation-induced transformation of murine
During 1982–1990, we published additional papers [8,9,49 –
fibroblast cells (CH3/T101/2 clone).
53,58] showing that -TS inhibited the growth of other tumor cell
During the 1990’s, the Kline group published a series of
lines such as murine NB (NBP2) and rat glioma (C6) cells in
articles [12–18,23,35] on the mechanisms of growth inhibitory
culture, inhibited ligand-stimulated response of adenylate cyclase,
action of
-TS on tumor cells that generated increased interest
enhanced the effect of x-irradiation hyperthermia, cAMP and
in the anti-cancer potential of this form of vitamin E. In
sodium butyrate. We also showed that
-TS increased PKA ac-
addition, two in vivo studies on the role of -TS in the preven-
tivity [59] and reduced the expression of c-myc and H-ras [42,43]
tion of chemical-induced cancer in hamster buccal pouches
in tumor cells in culture. During this period, only a few studies on
were reported [62,63].
-TS and cancer were published by others. It was demonstrated
In 2000 –2002, the demonstration that IP administration of
that -TS inhibited the growth of human NB cells in culture and
-TS inhibited the growth of several tumor types in athymic
in nude mice [10] and reduced the growth of oral cancer cells in
mice by Malafa et al. [39 – 41], Neuzil et al. [19] and Weber et
hamster pouch [38]. Ripoll et al. demonstrated that -TS reduced
al. [20] is going to have considerable impact on further eval-
the growth of human prostate carcinoma cells (DU-145) in culture
uating the anti-cancer potential of -TS. Furthermore, Neuzil et
al. have also shown that
-TS treatment did not affect the
proliferation of several human normal cell lines while inhibit-
ing the growth of several human cancer cell lines [24]. This
should further support the idea that
-TS treatment exhibits
high specificity for inhibiting the proliferation of cancer cells.
Previous studies [60 – 63] together with a recent study pub-
lished by Wu et al. [64] may stimulate research on the role of
-TS in cancer prevention.
In vitro Data on
-TS-Induced Differentiation,
Inhibition of Proliferation and Apoptosis in
Cancer Cells
-TS induced differentiation, inhibition of cell proliferation
and cell death in murine B-16 melanoma cells in culture,
depending upon the concentration [7].
-TS also inhibited
growth in human melanoma cells [21], murine NB cells [8], rat
glioma cells [8], human NB cells [10], human prostate cancer
cells [11,18,31,36] human parotid carcinoma cells [22], human
breast cancer cells [14,15,17,32,35,45], virally transformed ro-
dent cancer cells [12], several cell lines of human hematopoitic
cancer [13,16,24,25], adenocarcinoma cells of lung (A549),
bronchiocarcinoma (BEAS-2B), several cell lines of colon car-
cinoma [24], human gastric carcinoma (SgC-7901) [26,27],
human pancreatic cancer cells [28], human cervical and ovary
cells [29] and human oral squamous cell carcinoma [30]. These
Fig. 2. Melanoma cells (105) were plated in Lux tissue culture dishes
data show that -TS can reduce the proliferation of tumor cells
(60 mm), and D- -tocopherol (vitamin E) acid succinate (soluble in
of different cellular origin. Concentrations used in these studies
ethanol) and sodium succinate plus ethanol were added to separate
varied from 10 –50
M, and treatment time varied from a few
cultures 24 hours after plating. Drugs and medium were changed at two
hours to a few days. The types of effect (differentiation, inhi-
and three days after treatment. Photomicrographs were taken four days
bition of proliferation and apoptosis) depended upon the con-
after treatment. Control culture contained fibroblastic cells as well as
centration of -TS, period of treatment, form of tumor cells and
round cells in clumps (a) Cultures treated with ethanol (1%) and
culture conditions. Lower concentrations can cause cell differ-
sodium acid succinate (5 to 6
g/mL) also exhibited fibroblastic
entiation, inhibition of proliferation, whereas higher concentra-
morphology with fewer round cells (b). Vitamin E acid succinate-
treated cultures [5
g/mL (c); 6
g/mL (d)] showed a dramatic change
tions can induce apoptosis in tumor cells. Longer treatment
in morphology.
450 [7].
times are needed for a maximal effect of -TS on cancer cells.
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-Tocopheryl Succinate and Cancer
In contrast to the growth-inhibitory effect of
-TS on cancer
in human breast cancer cells in vitro [32]. In order to avoid the
cells, this form of vitamin E failed to affect cell proliferation,
possibility of hydrolysis in the gut, the nonhydrolyzable ether
mitotic accumulation and chromosomal damage on three dif-
form of -TS (TSE) was synthesized by Farris et al. [33]. This
ferent cell lines of normal human fibroblasts [29,65], rodent
analog as well as
-TS caused growth inhibition in murine
fibroblasts [9], prostate epithelial cells [31] and other normal
leukemia cell lines (myeloid and lymphocytic), but they did not
cells (human peripheral monocyte cells, monocyte derived
affect the growth of normal bone marrow cells. In fact, the
macrophages, fibroblasts and umbilical vein endothelial cells,
growth of these normal cells was stimulated by
-TS and its
murine peritoneal macrophages, rat intestinal epithelial cells,
analog, TSE [33].
neonatal cardiomyocytes, neonatal hepatocytes and smooth
muscle cells [24]). However, it has been reported that -TS can
cause apoptosis in human umbilical vein endothelial cells in
MECHANISMS OF ACTION OF
-TS
culture [66]. It is interesting to note that even
-T at 50
M
concentration inhibited the growth of vascular smooth cell
Relation Between
-TS, Antioxidants, Antioxidation
proliferation in culture via inhibition of PKC [67]. This effect
Activity and Inhibition of Proliferation
was considered independent of antioxidant activity. These data
It has been reported that
-TS-induced inhibition of cell
suggest that
-TS is the most effective form of vitamin E for
proliferation in vitro requires that this molecule remains intact
reducing the proliferation of cancer cells and that at similar
[33]. Since -TS is not hydrolyzed by cancer cells in vitro [65],
concentrations it produces no significant effect on the prolifer-
the above suggestion appears rational. Since ethanol solublized
ation of most normal cells. The selectivity of
-TS effect on
-T did not exhibit anti-cancer activity in vitro [7,34,55], it has
cancer cells has not yet been fully recognized by oncologists.
been presumed that
-TS-induced inhibition of cell prolifera-
tion and apoptosis does not involve antioxidation activity.
In vivo Data on
-TS-Induced Growth Inhibition
Here, we propose that all antioxidants that inhibit the prolifer-
ation of cancer cells at concentrations higher than those pro-
Helson et al. demonstrated for the first time that I. P.
duced by
-TS may also not involve antioxidation mechanism
administration of -TS dissolved in ethanol (50 mg/kg of body
and that -TS induced growth inhibition in vivo in part may be
weight) for a five-day period markedly reduced the growth of
mediated via
-T. This is supported by the following observa-
human NB cells in athymic mice [10]. Another study reported
tions: (a) water soluble -T inhibited the proliferation of cancer
that a direct injection of
-TS dissolved in sesame oil (250
cells at high concentrations in vitro [8,56,57]; (b) butylated
g/injection twice a week) for a period of four weeks caused
hydroxyanisole (which exhibits antioxidant activity similar to
regression of chemical-induced tumor in the oral cavity of
that of vitamin E, but without vitamin E activity) inhibited the
hamster [38]. Since then, no in vivo studies were initiated until
proliferation of melanoma cells and NB cells at concentrations
in 2000, when Malafa et al. showed that I.P. administration of
similar to that of -TS, but to a lesser degree than that produced
-TS dissolved in sesame oil (150 mg/Kg of body weight)
by -TS [8]; (c) trolox was less effective than -TS in both NB
reduced the growth of human breast cancer cells [39], murine
cells and melanoma cells in culture [8], but at higher concen-
melanoma cells [40] and murine colon carcinoma cells [41] in
trations can cause apoptosis in human colon cancer cells in
athymic nude mice. Weber et al. [20] reported that I.P. admin-
culture [70], and (d) treatment with
-T in vivo reduced the
istration of -TS dissolved in dimethylsulfoxide (DMSO) (100
growth of tumor less than that produced by
-TS treatment
mg/Kg of body weight, every third day) for a 12-day period
[20]. These studies suggest that
-TS in its intact form can
reduced the growth of human colon cancer in athymic mice by
exhibit most potent anti-cancer activity in vitro; however, in
80% and -T by only 35%. Similar observations were made by
vivo, part of the activity of
-TS may be mediated via
-T.
Neuzil et al. [19]. In addition to exhibiting anti-tumor activity
in vivo,
-TS also reduces colon cancer liver metastasis [41].
Studies on Cellular Uptake of
-TS
Oral [68] or sub-cutaneous [39,40] administration in rodents
was ineffective, suggesting that most of
-TS under these
In order to explain the mechanisms of the growth inhibitory
conditions may be hydrolyzed before entering into the blood
effect of
-TS in vitro, it was postulated that cancer cells may
stream. It has been observed that daily oral doses of
-TS in
accumulate more
-TS than normal cells [69]. To test this
humans are not fully hydrolyzed in the intestinal tract [69]. This
hypothesis, human cervical carcinoma cells (HeLa cells) and
was evidenced by the fact that -TS at a concentration of about
normal fibroblasts were incubated in the presence of
-TS (10
6
g/mL in comparison to a concentration of
-T of about 60
g/mL) for 4 and 24 hours, and then -TS was extracted, using
g/mL was detectable in the blood of these patients. It is
-TS as an internal standard. Results showed that both cancer
unknown whether this blood level of
-TS can be considered
cells and normal cells accumulated similar levels of -TS at 24
sufficient to inhibit the growth of tumor cells in vivo. It has
hours after treatment (Table 1), suggesting that tumor cells
been reported that
-TS can readily bind with lipoprotein, and
have acquired an increased degree of sensitivity to
-TS [65].
this complex continues to maintain potent anti-cancer activity
It was interesting to note that -T was not detectable in the cell,
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-Tocopheryl Succinate and Cancer
Table 1. Accumulation of D- -Tocopheryl Succinate ( -TS)
Studies on Expression of Genes and their Products
in Human Cervical Cancer (HeLa cells) and Normal Human
and their Translocation after Treatment with
-TS
Fibroblasts after 24 Hours of Treatment with
-TS
In order to understand the mechanisms of action of -TS on
Accumulation of
-TS
cancer cells, it was necessary to investigate the effect of
-TS
( g/mg protein)
on expression of those genes that have been implicated in
Concentrations of
-TS
regulation of proliferation and apoptosis. Indeed, the results of
Fibroblasts
HeLa Cells
several studies revealed that the expression of certain genes and
20
g/mL (37.6
M)
their products are up- and down-regulated after treatment of
Experiment 1
1.07
1.23
tumor cells with growth inhibitory concentrations of -TS. The
Experiment 2
0.89
1.02
10
g/mL (18.8
M)
genes which were up-regulated included TGF- s and their
Experiment 1
1.38
1.87
products, and TGF-
type II receptor in human breast cancer
Experiment 2
1.04
0.93
cells [15,35,44,46], mitogen-activate protein kinase (MAPK),
-TS was extracted in hexane, and
-tocopheryl acetate was used as an internal
Erk1m MEK1 and JNK1, but not p38, and phosphorylation of
standard to determine the efficiency of extraction procedure. The recovery
transcriptional factors (c-jun, AFT-2 and Elk-1) [45]. Similar
efficiency was 55% to 75%. The levels of accumulation after treatment of cells
observations were made on human gastric cancer cells [46].
with
-TS for 24 hours were similar in both HeLa cells and normal fibroblasts.
Each measurement was repeated twice, and they were reproducible within the
The genes which were down-regulated include CD178 on the
same experiment [65].
cell surface of ovarian carcinoma [48], prostate-specific antigen
(PSA) in human prostate cancer cells at both the transcriptional
implying that there was no significant conversion of
-TS to
and translational levels [31], vascular endothelial growth factor
-T within the cell. A cellular concentration of about 0.5
(VEGF) [36,39] and c-myc and H-ras in murine NB cells and
g/106 cells, which was about 40 times lower than that added
melanoma cells [42,43].
to the growth medium, was sufficient to inhibit the proliferation
In addition to changes in gene expression, the activities and
of Hela cells.
levels of some gene products are increased, decreased or trans-
located after treatment with growth inhibitory concentrations of
-TS. For example, the activities of caspase-3 in Jurkat lym-
Studies on Adenylate Cyclase Response to Ligands
phoma cells [37], caspase-3, 6, 8, and 9, but not caspase-1 in
After
-TS Treatment
promyelocytic leukemia [25], PKA (cAMP-dependent kinase)
Adenylate cyclase (AC) mediates the action of prostaglan-
in the cytosolic fraction of B-16 melanoma cells [59] increased,
din E (PGE ) in inducing differentiation and inhibition of
whereas, the activities of PKC in vitro [71], PKC- subtype in
1
1
proliferation in NB cells and of melanocyte-stimulating hor-
human Jurkat lymphoma cells by increasing protein phospho-
mone (MSH) in regulating proliferation and differentiation in
tase 2A (PP2A) activity [19], basal and PGE -stimulated AC in
1
melanocytes. Growth inhibitory concentrations of vitamin E
NB cells [9] and basal and MSH-stimulated AC activity in
succinate inhibited basal, PGE -stimulated AC in NB cells [9],
B-16 melanoma [58] cells were decreased.
-TS causes trans-
1
MSH-stimulated AC in melanoma cells [58] and sodium fluo-
location of Fas protein from the cytoplasm to plasma mem-
ride (NaF)- and forsoklin-stimulated AC in both NB cells and
brane [14]. It also inhibits activation of NF-k
and DNA-
melanoma cells in culture. These data suggest that -TS inhib-
binding activity of activated NF-k [72,73]. -TS also reduces
ited the activity of GTP-binding protein (Gs) and the catalytic
transcriptional activation of tumor necrosis factor-
(TNF- )
subunit of AC. These effects of
-TS are not related to its
[47]. The Kline group has proposed that -TS-induced apopto-
growth-inhibitory effect, because PGA , which inhibited the
sis in human breast cancer cells is mediated via Fas signaling
2
proliferation of melanoma cells, did not inhibit MSH-stimu-
pathway [14]. The most remarkable observation was that -TS
lated AC activity. The fact that butylated hydroxyanisole,
treatment induced Fas-sensitivity into Fas-resistant human
which inhibited the proliferation of NB cells, did not affect basal
breast cancer cells. Fas, also referred to as Apo-1 or CD 95, can
or PGE -stimulated AC activity in NB cells, suggests that inhibi-
induce apoptosis upon trimerization with Fas ligand (CD95L)
1
tion of PGE -stimulated AC by -TS is not due to its antioxidant
or upon cross-linking with Fas specific antibodies [17]. Weber
1
action.
-TS did not affect the proliferation of normal murine
et al. have proposed that
-TS-induced apoptosis in cancer
fibroblasts in culture, but it inhibited PGE -simulated AC activity
cells is independent of p53 and p21 [20]. This is in contrast to
1
[9]. These data suggest that -TS-induced inhibition of AC activ-
trolox and 5-FU which induces apoptosis via p53 and p21 [70].
ity in vitro is not related to inhibition of proliferation of cancer
Others have reported that -TS increases the expression of wild
cells or to proliferation of normal fibroblasts. The significance of
type p53, but decreases the expression of mutated p53 in
-TS-induced inhibition of AC activity is unknown. Since PGs for
chemical-induced tumor in hamster buccal pouches [63].
most cells and MSH for melanocyte can act as tumor promoters,
The levels of TGF- in human breast cancer cells increased
the above effect of -TS may be more relevant to cancer preven-
[44], whereas the levels of VEGF in human prostate cancer
tion than to cancer treatment.
cells in vitro [36] and breast cancer cells in vivo [39] and PSA
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-Tocopheryl Succinate and Cancer
in human prostate cancer cells [31] decreased after treatment
-TS Enhances the Effect of Hyperthermia on
with growth inhibitory concentrations of
-TS.
Tumor Cells
More recently, analysis of our data using gene array tech-
Hyperthermia is used as an experimental cancer therapy in
nique has allowed us to propose a novel concept with respect to
the treatment of primarily local solid tumors. It has been
the relationship between changes in gene expressions and
reported
-TS at a growth inhibitory concentration in combi-
growth inhibition after treatment of NB cells with
-TS (our
nation with hyperthermia at 43°C enhanced the growth-inhib-
unpublished observation). For example, alterations in the ex-
itory effect of hyperthermia on NB cells in a synergistic manner
pression of different sets of genes occurred that were unique
[50,51]. Even at a lower temperature of 41°C, the combination
either to a non-growth inhibitory or a growth inhibitory con-
of -TS and heat was more effective than the individual agents.
centration of
-TS. In addition, changes in expression of dif-
Butylated hydroxyanisole, an antioxidant without vitamin E
ferent sets of genes that were common to both non-growth
properties, also enhanced the effect of hyperthermia but to a
inhibitory and growth inhibitory concentrations of
-TS were
lesser degree that produced by -TS. These data suggest that in
found. These data suggest that profound changes in gene ex-
presence of
-TS, hyperthermic temperature can be reduced
pression can occur without any significant alterations in growth
from currently used temperatures of 42.5– 43 to 41°C without
or morphology of NB cells after treatment with a non-growth
sacrificing its efficacy on cancer cells. The currently used
inhibitory concentration of -TS. They also suggest that not all
temperatures of about 43°C produced burns to normal tissue
changes in gene expression that are observed after treatment
and such high temperatures cannot be given whole-body be-
with growth-inhibitory concentrations of
-TS are related to
cause of unacceptable side effects.
growth inhibition.
-TS Enhances the Effect of Chemotherapeutic
Agents on Cancer Cells without Affecting the
-TS in Combination with Dietary Micronutrients
Proliferation of Most Normal Cells
on Cell Proliferation
-TS enhanced the growth-inhibitory effect of several che-
-TS in combination with dietary micronutrients such as
motherapeutic agents on cancer cells in culture. For example,
retinoic acid, vitamin C and polar carotenoids is more effective
-TS enhanced the effect of adriamycin on human prostate
in reducing the proliferation of human melanoma cells [21] and
carcinoma cells [11], human glioma and Hela cells (unpub-
human parotid acinar carcinoma cell and immortalized acinar
lished observations); the effect of cis-platin, tamoxifen and
cells [22] in culture than the individual agents. This suggests
decarbazine (DTIC) on human melanoma cells [21] and human
that a combination of above agents rather than a single agent
parotid acinar carcinoma cells [22], the effect of doxorubicin on
murine leukemia cell lines [33]. However, -TS did not modify
should be considered as an adjunct to standard cancer treatment
the effect of adriamycin on the growth of human normal
for any clinical study.
fibroblasts (unpublished observations), but it protected bone
marrow cells against the lethal effect of doxorubicin [33]. Thus,
-TS can enhance the efficacy of some chemotherapeutic
Modification of Radiation Damage on Cancer and
agents selectively on cancer cells. More recently, we have
Normal Cells by
-TS
demonstrated that statins with a closed-ring structure such as
Ionizing radiation is commonly used as one of the standard
mevastatin inhibited the growth of NB cells by inhibiting
cancer treatment modalities; therefore, we have investigated the
proteasome activity, and this effect of mevastatin was enhanced
effect of
-TS in combination with radiation on normal and
by
-TS [74]. A recent study has shown that a mixture of
tumor cells. A growth inhibitory concentration of
-TS in
micronutrients (vitamin C, -TS and beta-carotene) potentiates
combination with x- or -irradiation reduced the growth of NB
the growth-inhibitory effects of paclitaxel and carboplatin in
cells more than that produced by individual agents alone [49].
human lung cancer cells in culture [75].
It also has been reported that a growth inhibitory concentration
of
-TS enhanced radiation-induced chromosomal damage in
-Tocopheryl Succinate Enhances the Effect of
human cervical cancer cells, but protected normal human fi-
Biological Response Modifiers on Cancer Cells
broblasts against such damage [65]. This form of vitamin E also
It has been reported that
-TS at a growth inhibitory con-
increased radiation-induced delay in mitotic accumulation in
centration can enhance the levels of cAMP-induced differenti-
human cervical cancer and ovary carcinoma cells without caus-
ation of murine NB cells [52,54] and murine melanoma cells
ing similar changes in human normal fibroblasts [29]. These
[53] in culture. -TS also enhanced the growth inhibitory effect
data suggest that
-TS can enhance the effect of irradiation on
of sodium butyrate, a 4-carbon fatty acid, on murine NB cells
cancer cells, but it can protect normal cells against some of the
in culture [52].
-TS in combination with other dietary micro-
toxicities.
nutrients (vitamin C, carotenoids and retinoic acid) may be
JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION
113

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-Tocopheryl Succinate and Cancer
more effective than the individual agents [21, 22]. This form of
including
-TS in combination with radiation therapy for the
vitamin E also enhanced the effect of
-interferon [21] on
treatment of breast cancer after surgical removal of a tumor
tumor cells in culture. This is a novel concept in the sense that
[79], and Kochupillai’s group has used a similar approach in
it can modify the effect of some physiological substances in the
combination with chemotherapy for the treatment of human
body, because in the past, it has been presumed that vitamin E
non-small cell lung carcinoma [80]. Initial results were encour-
acts as an independent agent in modifying cellular functions.
aging and showed that the combination treatment did not in-
Turley et al. have reported that the combination of
-TS plus
terfere with the efficacy of radiation or chemotherapy in cancer
anti-Fas increased apoptosis in Fas-resistant human breast can-
cells.
cer cells [17]. Weber et al. have shown that the combination of
-TS and tumor necrosis factor-related apoptosis-inducing li-
gand (TRAIL) was more effective than the individual agents in
CONCLUSIONS AND
inducing inhibition of proliferation and apoptosis in vitro and in
FUTURE DIRECTION
vivo without affecting the proliferation of normal tissues [20].
Results discussed above suggest that
-TS inhibits the pro-
Proposed Mechanisms of Damage to Cancer Cells
liferation of rodent and human cancer cells without affecting
When
-TS is Combined with Radiation or
the proliferation of most normal cells. In addition, they also
Chemotherapeutic Agents
show that -TS when used in combination with some standard
and experimental cancer therapeutic agents may enhance their
Pre-treatment of cancer cells with high doses of
-TS can
growth-inhibitory effect on cancer cells, while protecting nor-
cause damage by diverse mechanisms that include Fas-signal
mal cells against some of their toxicities. Since it has been
pathway [14,17], anti-angiogenesis [36,39], up-regulation of
demonstrated that
-TS in combination with dietary micronu-
wild type p53 and down regulation of mutant p53 [63], activa-
trients (retinoic acid, vitamin C and carotenoids) is more ef-
tion of caspase activity [25,37], inhibition of PKC activity
fective in reducing the proliferation of tumor cells in culture
[25,37], inhibition of activation of NF-k
and DNA binding
than the individual agents and in enhancing the effect of some
activity of activated NF-k
[72,73], down regulation of onco-
chemotherapeutic agents on these cells, we have recommended
genes, c-myc and H-ras [42,43]. High expression of c-myc and
the use
-TS in combination with dietary micronutrients as an
H-ras increases the radioresistance of cancer cells [76,77].
adjunct to standard therapy in the treatment of cancer [66].
Since -TS down-regulates these genes in cancer cells [42,43],
Although preliminary clinical studies using
-TS in combina-
pre-treatment of these cells with
-TS is expected to increase
tion with dietary micronutrients as an adjunct to standard
the sensitivity of cells to x-irradiation. 5-FU, a commonly used
chemotherapy appear encouraging, randomized double-blind-
chemotherapeutic agent, induced apoptosis in cancer cells via
placebo control trials, using high doses of multiple micronutri-
p53 and p21 [70], whereas
-TS produced such an effect by
ents including -TS as an adjunct to standard cancer therapy as
different mechanisms [14,17,36,39]. Therefore, the combination
well as experimental therapy (hyperthermia and some biolog-
of -TS and 5-FU would be more effective in inducing apoptosis
ical response modifiers), should be initiated. In basic research,
in cancer cells than the individual agents. It is unknown whether
it is essential to identify additional genes that initiate damage in
-TS when given after irradiation or chemotherapeutic agents
cancer cells as a function of time (a few minutes to a few days)
would inhibit repair of damage; however, retinoic acid has been
after treatment with
-TS. Although
-TS does not affect the
shown to inhibit the repair of radiation-induced potential lethal
proliferation of most normal cells, analogous studies should be
damage in cancer cells [78]. It has been reported that -TS can act
performed on normal counterpart cells in order to establish
as an anti-angiogenesis agent in vivo [36,39], whereas radiation or
whether normal cells show any alterations in gene expression.
chemotherapeutic agents do not; therefore, the combination of two
This is particularly important, because our recent study (un-
may be more effective in reducing the growth of cancer cells than
published observation) has shown that a non-growth-inhibitory
the individual agents. These data suggest that a combination of
concentration of
-TS markedly alters the expression of many
-TS with radiation or chemotherapeutic agents is more effective
genes in neuroblastoma cells, some of which exhibit changes
than the individual agents, because their mechanism of action on
similar to those produced by a growth-inhibitory concentration
tumor cells is different.
of
-TS.
Clinical Studies with
-TS Alone or in Combination
with Dietary Micronutrients as an Adjunct
Standard Therapy
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