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D-Alpha-Tocopheryl Succinate (Vitamin E) Enhances
Radiation-Induced Chromosomal Damage Levels in
Human Cancer Cells, but Reduces it in Normal Cells
Bipin Kumar MDa, Mitra N. Jhab, William C. Cole PhDa, Joel S. Bedford DPhilb & Kedar N.
Prasad PhD, FACNa
a Center for Vitamins and Cancer Research, Department of Radiology, University of
Colorado Health Sciences Center, Denver (B.K., W.C., K.P.), Colorado
b Department of Radiological Health Sciences, Colorado State University, Fort Collins
(M.N.J., J.S.B.), Colorado
Published online: 26 Jun 2013.
To cite this article: Bipin Kumar MD, Mitra N. Jha, William C. Cole PhD, Joel S. Bedford DPhil & Kedar N. Prasad PhD,
FACN (2002) D-Alpha-Tocopheryl Succinate (Vitamin E) Enhances Radiation-Induced Chromosomal Damage Levels in
Human Cancer Cells, but Reduces it in Normal Cells, Journal of the American College of Nutrition, 21:4, 339-343, DOI:
10.1080/07315724.2002.10719232
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Original Research
D-Alpha-Tocopheryl Succinate (Vitamin E) Enhances
Radiation-Induced Chromosomal Damage Levels in
Human Cancer Cells, but Reduces it in Normal Cells
Bipin Kumar, MD, Mitra N. Jha, William C. Cole, PhD, Joel S. Bedford, DPhil, and Kedar N. Prasad, PhD, FACN
Center for Vitamins and Cancer Research, Department of Radiology, University of Colorado Health Sciences Center, Denver
(B.K., W.C., K.P.), Department of Radiological Health Sciences, Colorado State University, Fort Collins (M.N.J., J.S.B.),
Colorado
Key words: irradiation, radiation therapy, carcinoma, chromatid damage
Objective: The purpose of this study was to measure and compare the effect of d-␣-tocopheryl succinate
(␣-TS) in modifying radiation-induced chromosomal damage in human normal cells and cancer cells in
culture.
Methods: Three human normal fibroblast cell lines (GM2149, AG1522 and HF19) and three human cancer
cell lines, cervical cancer (HeLa) and ovarian carcinoma cells (OVG1 and SKOV3) were treated with ␣-TS (37.6
␮M) 20 hours before 100 cGy ␥-irradiation. After 30 minutes of irradiation, colcemid was added and cells were
fixed. One hundred randomly selected metaphase cells were scored for the presence of chromatid gaps and
breaks. To study the cellular accumulation of ␣-TS, cells were incubated in the presence of ␣-TS (18.8 and 37.6
␮M) for 24 hours, and ␣-TS was extracted with hexane using ␣-tocopheryl acetate as an internal standard. The
levels of ␣-TS were determined by HPLC.
Results: Results showed that ␣-TS induced chromosomal damage in both human cervical cancer cells and
ovarian cancer cells, but not in human normal fibroblasts in culture. In addition, ␣-TS enhanced the level of
radiation-induced chromosomal damage in cancer cells, but it protected normal cells against such damage. Both
cancer cells and normal cells accumulated similar levels of ␣-TS, suggesting that increased sensitivity of cancer
cells to ␣-TS is acquired during transformation.
Conclusion: The use of ␣-TS during radiation therapy may improve the efficacy of radiation therapy by
enhancing tumor response and decreasing some of the toxicities on normal cells.
induce chromosomal damage in both normal and cancer cells;
INTRODUCTION
however, it is unknown whether ␣-TS can modify this effect of
Several studies on the radioprotective effects of vitamin E
on normal cells in animals have been published [1–9]. We have
reported that ␣-tocopheryl succinate (␣-TS), the most effective
form of vitamin E [10,11], enhances the growth-inhibitory
effect of x-irradiation on neuroblastoma cells in culture [12].
Recently, we have shown that ␣-TS increases the levels of
radiation-induced decrease in mitotic accumulation in human
cervical carcinoma cells and ovarian carcinoma cells in culture,
but it does not modify this effect of irradiation in normal
fibroblasts in culture [13]. Ionizing radiation is well known to
irradiation in cancer cells and normal cells. It is also unknown
whether ␣-TS-induced damage in cancer cells is due to in-
creased accumulation of ␣-TS in these cells.
We now report that ␣-TS by itself induces chromosomal
damage in cancer cells, but not in normal cells in culture. In
addition, it enhances the levels of ␥-irradiation-induced chro-
mosomal damage in cancer cells, whereas it protects normal
cells against such damage. Both normal and cancer cells accu-
mulate similar levels of ␣-TS, suggesting that increased sensi-
tivity of cancer cells to ␣-TS is acquired during transformation.
Address reprint requests to: Kedar N. Prasad, Ph.D., University of Colorado Health Sciences Center, 4200 East 9th Ave, Denver, CO 80262-0278. E mail:
Kedar.Prasad@UCHSC.edu
Journal of the American College of Nutrition, Vol. 21, No. 4, 339–343 (2002)
Published by the American College of Nutrition
339

Vitamin E and Chromosomal Damage
Statistical Analysis
MATERIALS AND METHODS
Each experiment was repeated twice. The significant differ-
ence between control and experimental groups was determined
by one-tail Student’s t test at p ϭ 0.05.
Cell Culture
Human cervical carcinoma cells (HeLa cells from Dr. L.J
Tolmach) ovarian carcinoma cells (OVG1 from Drs J.B. Mitch-
ell and J.A. Cook, and SKOV3 from Dr. L. Smith) and human
normal skin fibroblasts (GM 2149 from the NIGMS Human
Genetic Mutant Cell Repository, AG1522 from the NIA Cell
Repository and HF19 from Dr. D. Goodhead) were grown in
culture as described earlier [13].
RESULTS
Results showed that treatment with ␣-TS (20 ␮g/mL or 37.6
␮M) for a period of 20 hours increased the level of chromo-
somal damage (chromatid gaps and breaks) in HeLa cells and
ovarian carcinoma cells, but not in three lines of normal human
fibroblasts (Fig. 1). Solvent treatment did not alter chromo-
somal damage in cancer cells or normal fibroblasts in compar-
ison to untreated control cells (data not shown). In cancer cell
lines, the differences between untreated or solvent treated con-
trol and ␣-TS treated cells were significant at p Ͻ 0.05. In
addition, ␣-TS treatment 20 hours before ␥-irradiation en-
hanced the level of radiation-induced chromosomal damage in
all tumor cell lines. On the other hand, a similar treatment with
␣-TS reduced radiation-induced chromosomal damage in all
normal human fibroblast cell lines (Fig. 1). Solvent treatment
did not alter radiation-induced chromosomal damage either in
cancer cells or normal fibroblasts (data not shown). In both
cancer cells and normal fibroblasts, the differences between
irradiated cells and cells treated with ␣-TS and irradiation were
significant at p Ͻ 0.05. It should be pointed out that all cancer
cell lines are of epithelial origin; therefore, the observations
made on fibroblasts may or may not be relevant to normal
human epithelial cells.
In order to establish whether the higher sensitivity of cancer
cells to ␣-TS is related to the increased accumulation of this
vitamin E, the levels of ␣-TS in cancer cells and normal
fibroblasts were determined by HPLC after incubation of cells
in the presence of 18.8 or 37.6 ␮M of ␣-TS for 24 hours at 37°.
Results showed that HeLa cells and normal cells after 24 hours
of incubation accumulated similar levels of ␣-TS (Table 1).
The level of ␣-TS was undetectable in both cancer cells and
normal fibroblasts, suggesting that these cells do not convert
␣-TS to ␣-tocopherol in any significant amounts within 24
hours. These results indicate that increased sensitivity of cancer
cells to ␣-TS is acquired during transformation and is not due
to enhanced accumulation of this form of vitamin E.
Treatment of Cells and Assay of
Chromosomal Damage
The procedures for making solutions of d-␣-tocopheryl suc-
cinate (Henkel, Chicago), colcemid (Sigma, St. Louise) and
their storage have been published earlier [13]. In brief, ␣-TS
was dissolved in ethanol at a concentration of 5 mg/mL. Cells
were treated with ␣-TS (20 ␮g/ml or 37.6 ␮M) for 20 hours
before ␥-irradiation (100 cGy). The above concentration of
␣-TS and treatment period were selected because this concen-
tration under the above experimental conditions inhibits the
growth of cancer cells, but not of normal fibroblasts in culture
[13]. It has been shown that a daily oral intake of 800 IU ␣-TS
increases plasma levels of vitamin E (␣-tocopherol, 60 ␮g/mL
and ␣-TS, 6 ␮g/mL) [14]. The basal level of ␣-tocopherol in
plasma is about 6–10 ␮g/mL. After 30 minutes of irradiation,
colcemid (0.1 ␮g/ml) was added and one hour later the cells
were fixed with 3:1 methanol and acetic acid for an hour and
stained with Giemsa. The slides were randomized and coded to
ensure that the observer was unaware of conditions of treatment
at the time of scoring the chromosomal damage. For aberration
frequency, 100 randomly selected metaphase-like cells were
scored for the presence of chromosomal aberrations (chromatid
gaps and breaks) according to the criterion suggested by Sav-
age [15].
Intracellular Uptake of A-TS
To study the uptake of ␣-TS by cancer cells and normal
cells, cells were incubated in the presence of ␣-TS (18.8 and
36.6 ␮M) for 24 hours and then removed and washed with
PBS. Vitamin E was extracted with hexane using ␣-tocopheryl
acetate (␣-TA) as an internal standard. The levels of ␣-TS and
␣-TA were determined by HPLC using a C18 column (4.6
mm ϫ 250 mm, 5 ␮m particle size) eluted with acetonitrile:
MeOH (0.028% TFA) 60:40 (v/v) at a flow rate of 2.0 mL/minute.
The level of each form of vitamin E was determined from a
standard curve and expressed as ␮g of vitamin E/mg protein.
Protein was determined by the method of Lowry et al. [16].
DISCUSSION
The present study shows that ␣-TS treatment induces chro-
mosomal damage in cancer cells, but not in normal cells. This
selective effect of ␣-TS on human cancer cells is consistent
with the results published earlier by us and others on other
criteria of damage [10,11,14,17–20] and in animal tumor mod-
els [21,22]. To determine whether the increased sensitivity of
340
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Vitamin E and Chromosomal Damage
Table 1. Accumulation of D-␣-Tocopheryl Succinate (␣-TS)
in Human Cervical Cancer (HeLa cells) and Normal Human
Fibroblasts after 24 Hours of Treatment with ␣-TS
Accumulation of ␣-TS
(␮g/mg protein)
Concentrations of ␣-TS
Fibroblasts
HeLa Cells
20 ␮g/mL (37.6 ␮M)
Experiment 1
Experiment 2
1.07
0.89
1.23
1.02
10 ␮g/mL (18.8 ␮M)
Experiment 1
Experiment 2
1.38
1.04
1.87
0.93
␣-TS was extracted in hexane, and ␣-tocopheryl acetate was used as an internal
standard to determine the efficiency of extraction procedure. The recovery
efficiency was 55% to 75%. The levels of accumulation after treatment of cells
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
same experiment.
fibroblasts against such damage. Solvent treatment does not
modify radiation damage either in cancer cells or normal fi-
broblasts in culture. The radiosensitizing effect of ␣-TS is
consistent with the results published earlier, in which treatment
of tumor cells with ␣-TS before x-irradiation enhances the level
of radiation-induced growth inhibition [12] and radiation-in-
duced decrease in mitotic accumulation [13]. The radioprotec-
tive effect of ␣-TS on normal cells is also consistent with
several studies reported earlier with other forms of vitamin E
[1–9]. Most of these studies have focused on investigating the
effect of vitamin E in modifying radiation response either in
normal cells or in cancer cells. The present study is unique in
the sense that it has compared the effect of ␣-TS in modifying
radiation response on cancer cells and normal cells under
similar experimental conditions. It should be pointed out that
tumor cells used in this study are of epithelial origin, whereas
normal cells are fibroblasts. Nevertheless, fibroblasts are also
damaged during radiation therapy; therefore, if similar obser-
vations are made in vivo, the use of ␣-TS may improve the
efficacy of radiation therapy by increasing tumor response and
decreasing some of the toxicities.
Other antioxidant micronutrients such as vitamin C [23,24],
all-trans-retinoic acid [25,26], retinyl palmitate (vitamin A) and
␤-carotene [27] when given before irradiation also enhanced
radiation-induced growth inhibition in tumor cells in culture
and in vivo without causing toxicity to normal cells in vivo. A
recent study has reported that administration of multiple anti-
oxidants (vitamin A, E and C) before and after radio-immuno-
therapy reduced the magnitude of myelosuppression without
interfering with its efficacy on tumor cells [28]. Another study
has shown that vitamin C, vitamin E acetate and ␤-carotene in
combination with mitomycin and irradiation were more effec-
tive in reducing the growth human of leukemic cells (HL-60) in
culture than the individual agents [29]. Limited clinical trials in
humans have reported enhancement of the efficacy of radiation
Fig. 1. Effect of d-␣-tocopheryl succinate (␣-TS) on the level of
radiation-induced chromosomal damage in human cervical cancer
(HeLa cells), ovarian carcinoma cell lines (OVG1 and SKOV3) and in
human normal skin fibroblasts (GM2149, HF19 and AG1522). ␣-TS
treatment alone increased chromosomal damage in all three cancer cell
lines, but not in any normal cell lines. ␣-TS treatment also enhanced the
levels of radiation-induced chromosomal damage in cancer cells but it
protected normal cells against such damage. The bar is standard error
of the mean; the difference between control and experimental groups in
cancer cells, and between control (irradiation alone) and experimental
groups (irradiation plus ␣-TS) is significant at p Ͻ 0.05.
cancer cells to ␣-TS is related to the enhanced accumulation of
this form of vitamin E in these cells, cancer cells and normal
fibroblasts were incubated in the presence of ␣-TS for 24 hours,
and cellular levels of ␣-TS were determined by HPLC. Results
showed that both cancer cells and normal cells accumulated
similar levels of ␣-TS. This suggests that the increased sensi-
tivity of cancer cells to ␣-TS in comparison to normal cells is
acquired during transformation.
When ␣-TS is given before irradiation it increases the level
of radiation-induced chromosomal damage in human cervical
carcinoma and ovarian carcinoma, but protects normal human
JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION
341

Vitamin E and Chromosomal Damage
therapy and chemotherapy with antioxidant micronutrients in
patients with small-cell lung carcinoma [30,31] and breast
cancer [32].
micronutrients before radiation therapy may increase the effi-
cacy of this treatment by increasing tumor response and de-
creasing some of the toxicities on normal cells [14,41]. Well-
designed clinical trials with multiple micronutrients, which
include high dose antioxidants such as vitamins A, C and E,
and carotenoids, are needed to substantiate the above hypoth-
esis.
The exact mechanisms of differential modification of the
effect of irradiation by ␣-TS on chromosomal damage in nor-
mal and cancer cells are unknown. We propose that an admin-
istration of ␣-TS at high doses before irradiation initiates
damage in cancer cells as evidenced by the alterations in
expression of those genes and cell signaling systems that are
involved in regulation of growth and differentiation [11,17–
21,33–37]. They include decreased expression of c-myc, N-
myc, H-ras, mutated p53, tumor necrosis factor, transcriptional
factor E2F and Fas, and reduced activity of protein kinase C.
They also include increased expression of wild type p53, p21,
transforming growth factor ␤ (TGF-␤), and the connexin gene,
and activation of caspase. Since retinoic acid has been shown to
reduce the repair of potential lethal damage [25], it is possible
that ␣-TS may have similar effects on the repair of radiation
damage in cancer cells. In addition, cancer cells, in general,
have lower intracellular pH than normal cells; therefore, ␣-TS
may not be able to perform its antioxidant function. This would
then allow free radicals generated during irradiation to increase
damage in cancer cells initiated by ␣-TS. In contrast to cancer
cells, ␣-TS does not cause any chromosomal damage in normal
cells, and at normal intracellular pH, ␣-TS continues to perform
its antioxidant action. It is also possible that ␣-TS may enhance
the rate of repair of potential radiation damage in normal cells.
Therefore, it is not surprising that ␣-TS protects normal cells
against radiation-induced chromosomal damage.
ACKNOWLEDGMENT
This study was supported by Shafroth Memorial Fund.
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Received July 19, 2001; revision accepted September 28, 2001.
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