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Nutrition and Cancer

Lycopene Inhibits Proliferation and Enhances Gap-Junction Communication of KB-1 Human Oral Tumor Cells
Orly Livny, Ilana Kaplan,* Ram Reifen, Sylvie Polak-Charcon,† Zecharia Madar and Betty Schwartz1
Institute of Biochemistry, Food Science and Nutrition, Faculty of Agricultural, Food and Environmental Quality Sciences, The Hebrew University of Jerusalem, Rehovot 76100,Israel; *Department of Oral Pathology and Medicine, School of Dental Medicine, Tel-Aviv University, Tel-Aviv, Israel; and †Institute of Pathology, Sheba Medical Center, Tel-Hashomer, Israel
ABSTRACT Cell-cell interaction via gap junctions is considered to be a key factor in tissue homeostasis, and its alteration is associated with the neoplastic phenotype. Experimental and epidemiologic datasuggest that carotenoids, particularly lycopene and -carotene, can reduce the risk of certain cancers. The aim of this study was to assess whether lycopene and -carotene interfere at some stage with the carcinogenic processes in human cancer cells derived from the oral cavity. KB-1 cells, originating from a human oral cavity tumor, were incubated with different concentrations of lycopene or -carotenedelivered via the cell culture media from stock solutions in tetrahydrofuran. Lycopene strongly and dose dependently inhibited proliferation of KB-1 human oral tumor cells. -Carotene was a far less effective growth inhibitor. Lycopene (3 and 7 mol/L) significantly upregulated both the transcription (P 0.005) and the expression (P 0.05) of connexin 43, a key protein in the formation of gap-junctionalcommunication. -Carotene (3 mol/L) tended to upregulate connexin 43 expression (P 0.07) and significantly affected transcription of connexin 43 at 7 mol/L (P 0.05). Gap-junctional communication measured by scrape-loading dye transfer and electron microscopy showed that lycopene enhanced gap-junctional communication between the cancer cells, whereas -carotene was less effective in this regard. Thepattern of cellular uptake and incorporation into cancer KB-1 cells differed significantly between the carotenoids. -Carotene was avidly and rapidly incorporated into KB-1 cells, whereas lycopene uptake into the cells took place after longer incubation periods and only at the highest concentrations. The results of the present study further support the hypothesis that carotenoids in general, andlycopene in particular, may be effective anticarcinogenic agents in oral carcinogenesis. J. Nutr. 132: 3754 –3759, 2002. KEY WORDS:
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Oral cavity cancer is the sixth most frequent cancer in the world. Some of the highest rates are indeveloping countries where up to 25% of all malignancies are found in the oral cavity (1). Although this neoplasia is treatable with surgery or radiotherapy in its early stages, most patients are diagnosed only at advanced stages of the disease. At these late stages, therapy outcomes have not dramatically improved in recent years. Reduced incidence of this disease may be attainable through preventivemeasures (2,3). Preventive strategies are designed to suppress, reverse or prevent the formation of premalignant lesions and their subsequent development through the multistep process of initiation, promotion and progression into squamous cell carcinoma (4,5). Epidemiologic studies suggest that a diet rich in lycopene is related to decreased risk of certain diseases, particularly cancers of thedigestive tract, prostate and pancreas, as well as cardiovascular disease (6). Most of the reports concerning the anticarcinogenic activity of carotenoids emphasize their ability
1 To whom correspondence should be addressed. E-mail: bschwart@agri.huji.ac.il

to be converted into vitamin A, which has been associated with differentiation and cancer regression (7,8). All-trans retinoic acid has been...