Dietary AntioxidantInduced Alterations in Gene Expression in Cancer Cells

Since high-dose vitamin A, vitamin C, vitamin E and carotenoids inhibit the growth of cancer cells but not of normal cells (16-20, 22-24, 26-43, 49), studies on the expression of genes that are involved in differentiation, growth regulation, trans

Table 11.2 Effects of retinoids, p-carotene, and vitamin E on gene expression in tumor cells in culture

Reduced gene expression and/or activity

Increased gene expression and/or activity

p53 mutant

p53 wild-type

c-myc

p21

H-ras

c-fos

Bcl2

c-jun

c-neu

HSP70

c-erB2

HSP90

VEGF

connexin

Phosphotyrosine kinase

TGF-p

Protein kinase C

MAP kinase

Caspase

Cyclin A, cyclin D, and their kinases

Tumor necrosis factor

Transcription factor E2F

Fas

Summarized from reviews (8, 10). Effects of retinoids, p-carotene, and a-tocopheryl succinate on gene expression and enzyme activity in various tumor cells in culture were studied. Alterations in gene expressions and enzyme activity were observed.

formation, and apoptosis have been carried out only in cancer cells. These studies reveal that retinoids, vitamin E, and p-carotene attenuate the levels of those cell-signaling systems and gene expressions that can lead to decreased cell proliferation rate, increased differentiation, and/or ap-optosis. They include expression of c-myc, H-ras (50, 51), N-myc (51), mutated p53 (27), protein kinase C (52, 53), caspase (54), tumor necrosis factor (55), transcriptional factor E2F (25), and Fas (24). Retinoids, vitamin E, and p-carotene enhance the levels of those cell signaling pathways and gene expression that can lead to reduced growth rate, increased differentiation, and/or apoptosis, and they include the expression of wild-type p53 (27) and p21 (32), transforming growth factor p (TGF-p) (22), and the connexin gene (28). The above changes (Table 11.2) in gene expression may be one of the major factors that account for the growth-inhibitory effects of these dietary antioxidant micronutrients on cancer cells. It should be pointed out that most of the effects of dietary antioxidant micronutrients such as vitamin A, vitamin C, vitamin E, and carote-noids on gene expression in cancer cells may not be due to their classical antioxidant action.

In addition to changes in gene expression, a novel mechanism of action of a-TS has been reported in an animal tumor model. a-TS inhibits the growth of tumor cells in vivo without affecting normal cells (33). It also reduces the expression of vascular endothelial growth factor (VEGF), and thus acts as an antiangiogenesis factor at a concentration that is not toxic to normal cells. It is unknown whether retinoids, vitamin C, and p-car-otene, which also inhibit the growth of cancer cells, can cause similar effects on angiogenesis in vivo.

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