By Lynn Keegan, RN, PhD, HNC, FAAN, and Gerald T. Keegan, MD, FACS
Cervical cancer is the second most common cancer worldwide and is a leading cause of cancer-related deaths in women in underdeveloped countries. Worldwide, approximately 500,000 cases of cervical cancer are diagnosed yearly.1,2 Invasive cervical cancer is more common in middle-aged and older women of poor socioeconomic status. There is a higher rate of incidence in African-American, Hispanic, and Native American women. Specific genotypes have been associated with the development of the malady.3
Etiology of Cervical Cancer
Although the cause of cervical cancer is unknown, there has been association of the disease with two types of human papilloma virus (HPV), both of which are transmitted sexually. Evidence of HPV is found in nearly 80% of cervical carcinomas. Human immunodeficiency virus (HIV) infection reduces the immune system’s ability to combat infection, including HPV, and thus increases the likelihood of the disease.4-6 It also has been established that women who smoke are twice as likely to develop cervical cancer.7 The authors of this paper have suggested that cigarette byproducts may affect the early evolution of HPV-related lesions, possibly by increasing the rate of cell turnover. It is likely that the actual cause of the disease is multifactorial and that the presence of the HPV induces the development of premalignant cells, which under the influence of oxidative stress and perhaps genetic6 and nutritional8 factors will further evolve into malignant and eventually invasive lesions. Some of these enabling factors may be reversible by the use of appropriate antioxidants.8
Mechanisms of Action
Although there are a number of studies on the mechanistic role of antioxidants in the prevention of the evolution of precancerous cervical cells into frank malignancy, the entire relationship has yet to be elucidated. Epidemiologic nutritional studies suggest that higher dietary consumption and circulating levels of certain micronutrients may be protective against cervical cancer. Low levels of essential antioxidants in the circulation have been found to be associated with an increased risk of cancer.1 It is possible that the infection with HPV induces an oxidative stress in cervical cells which then in association with other factors proceeds to the development of premalignant cells including cervical intraepithelial neoplasia (CIN) and thence to frankly malignant dedifferentiation. Antioxidants are theorized to reverse this process by a variety of mechanisms.
A study was undertaken in Japan to investigate the effect of the major tea polyphenol, (-)-epigallocatechin gallate (EGCG) in cervical carcinogenesis. This study suggested that EGCG prevents the carcinogenesis of cervical cancer, induces apoptosis, and inhibits telomerase activity. The effect by EGCG treatment may be associated with the induction of apoptosis and telomerase inhibition in early cervical lesions.9 A related study assessed the effect of EGCG on epidermal growth factor receptor (EGFR). EGFR signaling activation is absolutely required for cervical cell proliferation and is a promoter of the disease. Thus, EGFR-inhibitory agents may be of therapeutic value. The authors demonstrated that EGCG treatment caused apoptosis of the abnormal cervical cells. In addition, they found EGCG acts simultaneously at multiple levels to inhibit epidermal growth factor (EGF)-dependent signaling. These results suggest that EGCG acts to selectively inhibit multiple EGF-dependent kinases to inhibit cell proliferation.10 A study from South Korea reinforced the anti-proliferative effects of EGCG. This study of HPV-associated cervical cancer cells in tissue culture demonstrated both a gene-regulatory role for EGCG as well as inhibition of cervical cancer cell growth through the induction of apoptosis and cell cycle arrest.11 Another study from South Korea that investigated clinical efficacy of green tea extracts EGCG in patients with HPV-infected cervical lesions demonstrated that the extract in a form of ointment or a capsule was effective in treating cervical lesions. These findings suggest that green tea extracts can be a potential therapy regimen for patients with HPV-infected cervical lesions.12
Cofactors, such as nutritional factors, may be necessary for viral (HPV) progression to neoplasia. Many studies have suggested that higher dietary consumption and circulating levels of certain micronutrients might be protective against cervical neoplasia. A study was undertaken to evaluate the role of vitamin A and carotenoids on HPV persistence by comparing women with intermittent and persistent infections. The results showed a 56% reduction in HPV persistence risk observed in women with the highest plasma cis-lycopene concentrations compared with women with the lowest plasma cis-lycopene concentrations. These data suggest that vegetable consumption and circulating cis-lycopene may be protective against HPV persistence.13 A very interesting finding, possibly applicable to the treatment of invasive carcinoma of the cervix, was the effect of d-alpha-tocopheryl succinate (alpha-TS) in modifying radiation-induced chromosomal damage in human normal cells and cancer cells in culture. The use of this vitamin E-like substance during radiation therapy possibly could improve the efficacy of radiation therapy in cervical cancer by enhancing tumor response and decreasing some of the toxicities on normal cells.14
Another antioxidant, resveratrol, is a polyphenol isolated from the skins of grapes. This substance has been shown to significantly alter the cellular physiology of tumor cells, as well as block the process of initiation and progression. One mechanism for the intracellular actions of resveratrol involves the suppression of prostaglandin (PG) biosynthesis. The involvement of PGs and other eicosanoids in the development of human cancer is well-established. A study using two human cervical tumor cell lines demonstrated that resveratrol alters both cell cycle progression and the cytotoxic response to ionizing radiation.15
A cross-sectional study was undertaken to investigate the comparative plasma concentrations of three potent antioxidants—coenzyme Q10 (CoQ10), alpha-tocopherol, and gamma-tocopherol—in women with normal Pap smears and patients with a biopsy-confirmed histopathological lesion diagnosed as CIN or overt cervical cancer. After controlling for age and smoking, an inverse association between histological grades of epithelial lesions and both plasma CoQ10 and alpha-tocopherol concentrations was observed. The low plasma concentration of CoQ10 in the women with cervical lesions was believed to be secondary either to deficient dietary intake or a decrease in endogenous CoQ10 biosynthesis. The de- creased CoQ10 biosynthesis possibly reflected increased utilization of this enzyme as a result of free radical reactive oxygen species-induced oxidative stress.16 The extent of free radical-induced oxidative stress can be exacerbated by the decreased efficiency of antioxidant defense mechanisms.
To assess the extent of oxidative stress, Manju et al measured the levels of antioxidants superoxide dismutase (SOD), catalase (CAT), and ceruloplasmin, and evaluated tumor markers, such as aspartate transaminase, alanine transaminase, alkaline phosphatase, and total sialic acid levels, in circulation of women with cervical carcinoma. These data were compared with levels in age-matched controls. Low levels of SOD and CAT were observed in the circulation of cervical cancer patients.17
This effect was believed to be secondary to the increased utilization of these enzymes to scavenge lipid peroxides as well as their sequestration by tumor cells.1 This conclusion was verified by a case-control study that was conducted to investigate the status of circulating lipid peroxidation and the enzymic and nonenzymic antioxidants of cervical cancer patients. Plasma thiobarbituric acid reactive substances (TBARS), conjugated dienes (CD), and the levels of antioxidants such as reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione-S-transferase (GST), SOD, vitamin C, and vitamin E, were estimated in circulation of 30 patients and an equal number of age-matched normal subjects as control. The authors observed significantly elevated levels of plasma TBARS and CD and significantly lowered levels of GSH, GPx, GST, SOD, vitamin C, and vitamin E in cervical cancer patients as compared to controls. The study confirmed increased lipid peroxidation and possible breakdown of antioxidant status in patients with cervical carcinoma and suggested that the low levels of antioxidants may be due to their increased utilization to scavenge lipid peroxides as well as their sequestration by tumor cells.17
With the theory that oxidative stress is implicated in the etiology of many diseases, the antioxidants are thought to diminish oxidative stress. To this effect, researchers in Hong Kong evaluated the effects of ingested vitamins C (500 mg) and E (400 IU), alone and in combination, on biomarkers of plasma antioxidant status, lipid peroxidation, and lymphocyte DNA damage in 12 volunteers. The data showed no evidence of either a protective or deleterious effect on DNA damage, resistance of DNA to oxidant challenge, or lipid peroxidation. No evidence of a synergistic or cooperative interaction between vitamins C and E was seen, but further study is needed to determine possible interactive effects in a staggered supplementation cycle. Study of subjects under increased oxidative stress or with marginal antioxidant status would be useful. It would be of interest also to study the effects of these vitamins ingested with, or in, whole food to determine if they are directly protective at doses above the minimum required to prevent deficiency; if combinations with other food components are needed for effective protection; or if vitamins C and E are largely surrogate biomarkers of a "healthy" diet, but are not the key protective agents.18
An Austrian study monitored the dietary habits of 59 healthy, middle-aged men and women to assess the effect of supplementation with a natural phytonutrient preparation from fruits and vegetables on plasma levels of various antioxidant micronutrients and oxidative stress. Results found significant increases in blood nutrient levels after active supplementation for beta-carotene, vitamin C, vitamin E, selenium, and folate. Ranges measured after supplementation often fell into those associated with a reduced risk for disease. The researchers concluded that supplementation with mixed fruit and vegetable juice concentrates increased plasma levels of important antioxidant nutrients.19
Food Sources and Patterns of Usage for Antioxidants
A Spanish study of 41,446 healthy volunteers assessed the principal food sources of vitamin C, vitamin E, alpha-carotene, beta-carotene, lycopene, lutein, beta-cryptoxanthin, and zeaxanthin in an adult Spanish population. Foods that provided at least two-thirds of the studied nutrients were: fruits (mainly oranges) (51%) and fruiting vegetables (mainly tomato and sweet pepper) (20%) for vitamin C; vegetable oils (sunflower and olive) (40%), non-citrus fruits (10%), and nuts and seeds (8%) for vitamin E; root vegetables (carrots) (82%) for alpha-carotene; green leafy (28%), root (24%) and fruiting vegetables (22%) for beta-carotene; fruiting vegetables (fresh tomato) (72%) for lycopene; green leafy vegetables (64%) for lutein; citrus fruits (68%) for beta-cryptoxanthin; citrus fruits (43%) and green leafy vegetables (20%) for zeaxanthin.20
In the United States, the percentage of adults using any vitamin and mineral supplement daily increased from 23.2% in 1987 to 23.7% in 1992 to 33.9% in 2000. This pattern was consistent for both sexes, all race/ethnic groups, and adults age 25 and older. The increase in the percentage of daily users of multivitamins, vitamin A, and vitamin E was 10.5%, 1.2%, and 7.3%, respectively, from 1987 to 2000. Increases in daily use of vitamin C (3.3%) and calcium (6.1%) occurred between 1992 and 2000. All trend analyses were significant at P < 0.001. In the 2000 National Health Interview Survey, personnel queried the use of nonvitamin/nonmineral supplements for the first time. At that time, 6.0% of respondents reported using them daily.21
There are no specific contraindications of intake of antioxidants; however, excessive dosages of any one thing could be detrimental. For example, increased levels of vitamin C are linked to the formation of kidney stones and vitamin A is toxic in extremely high doses.
For some time we have suspected that socio-economic status relates to quality and type of food intake. Lack of education and motivation often results in poor food choices and the resultant health consequences. British researchers did a randomized trial comparing behavioral counseling with nutritional education counseling to increase fruit and vegetable consumption and associated biomarkers in 271 adults from a low-income neighborhood. The objective was to assess the impact of interventions on quality of life and health status, and associations between changes in fruit and vegetable consumption, plasma levels of vitamins C and E, and quality of life. The findings were that with reported increase in fruit and vegetable consumption, plasma vitamin C, E, and beta-carotene increased along with reported increased health. The researchers concluded that increases in fruit and vegetable intake and plasma vitamin levels may stimulate beneficial changes in physical health status in socioeconomically deprived adults.22
The literature clearly establishes both a protective and a therapeutic advantage in selected antioxidants including vitamins A, C, and E, CoQ10, EGCG, resveratrol, and vegetable lycopenes. Similarly, it may be contended that the higher incidence of disease in lower socioeconomic groups may be related to dietary deficiency of those same substances. There are a number of things women can do to deter the risk of cervical cancer, such as avoid smoking and second hand smoke; practice safe sex (the use of condoms prevents most sexually transmitted diseases including HPV, a common precursor of cervical cancer); and increase intake of antioxidants through foods and supplements.
Gerald T. Keegan, MD, is Emeritus Staff, Scott & White Clinic and Hospital, and former Professor of Surgery (Urology), Texas A&M University School of Medicine.
1. Manju V, et al. Oxidative stress and tumor markers in cervical cancer patients. J Biochem Mol Biol Biophys 2002;6:387-390.
2. National Library of Medicine. Medline Plus. Cervical cancer. Available at: www.nlm.nih.gov/medlineplus/cervicalcancer.html. Accessed June 6, 2004.
3. Deluca GD, et al. Human papillomavirus genotypes in women with cervical cytological abnormalities from an area with high incidence of cervical cancer. Rev Inst Med Trop Sao Paulo 2004;46:9-12. Epub 2004 Mar 29.
4. De Palo G. Cervical precancer and cancer, past, present and future. Eur J Gynaecol Oncol 2004;25:269-278.
5. Minkoff H, et al. Relationship between smoking and human papillomavirus infections in HIV-infected and -uninfected women. J Infect Dis 2004;189:1821-1828. Epub 2004 Apr 27.
6. Baay MF, et al. Human papillomavirus in a rural community in Zimbabwe: The impact of HIV co-infection on HPV genotype distribution. J Med Virol 2004; 73:481-485.
7. Harris TG, et al. Cigarette smoking, oncogenic human papilloma virus, Ki-67 antigen, and cervical intraepithelial neoplasia. Am J Epidemiol 2004;159:834-842.
8. Marshall K. Cervical dysplasia: Early intervention. Altern Med Rev 2003;8:156-170.
9. Yokoyama M, et al. The tea polyphenol, (-)-epigallocatechin gallate effects on growth, apoptosis, and telomerase activity in cervical cell lines. Gynecol Oncol 2004;92:197-204.
10. Sah JF, et al. Epigallocatechin-3-gallate inhibits epidermal growth factor receptor signaling pathway. Evidence for direct inhibition of ERK1/2 and AKT kinases. J Biol Chem 2004;279:12755-12762. Epub 2003 Dec 29.
11. Ahn WS, et al. A major constituent of green tea, EGCG, inhibits the growth of a human cervical cancer cell line, CaSki cells, through apoptosis, G(1) arrest, and regulation of gene expression. DNA Cell Biol 2003;22:217-224.
12. Ahn WS, et al. Protective effects of green tea extracts (polyphenon E and EGCG) on human cervical lesions. Eur J Cancer Prev 2003;12:383-390.
13. Sedjo RL, et al. Vitamin A, carotenoids, and risk of persistent oncogenic human papillomavirus infection. Cancer Epidemiol Biomarkers Prev 2002;11:876-884.
14. Kumar B, et al. D-alpha-tocopheryl succinate (vitamin E) enhances radiation-induced chromosomal damage levels in human cancer cells, but reduces it in normal cells. J Am Coll Nutr 2002;21:339-343.
15. Zoberi I, et al. Radiosensitizing and anti-proliferative effects of resveratrol in two human cervical tumor cell lines. Cancer Lett 2002;175:165-173.
16. Palan PR, et al. Plasma concentrations of coenzyme Q10 and tocopherols in cervical intraepithelial neoplasia and cervical cancer. Eur J Cancer Prev 2003;12: 321-326.
17. Manju V, et al. Circulating lipid peroxidation and antioxidant status in cervical cancer patients: A case-control study. Clin Biochem 2002;35:621-625.
18. Choi SW, et al. Vitamins C and E: Acute interactive effects on biomarkers of antioxidant defence and oxidative stress. Mutat Res 2004;551:109-117.
19. Kiefer I, et al. Supplementation with mixed fruit and vegetable juice concentrates increased serum antioxidants and folate in healthy adults. J Am Coll Nutr 2004;23:205-211.
20. Garcia-Closas R, et al. Dietary sources of vitamin C, vitamin E and specific carotenoids in Spain. Br J Nutr 2004;91:1005-1011.
21. Millen AE, et al. Use of vitamin, mineral, nonvitamin, and nonmineral supplements in the United States: The 1987, 1992, and 2000 National Health Interview Survey results. J Am Diet Assoc 2004;104:942-950.
22. Steptoe A, et al. Quality of life and self-rated health in relation to changes in fruit and vegetable intake and in plasma vitamins C and E in a randomised trial of behavioural and nutritional education counselling. Br J Nutr 2004;92:177-184.