Lycopene and 1,25‐dihydroxyvitamin d₃cooperate in the inhibition of cell cycle progression and induction of differentiation in hl‐60 leukemic cells

Abstract

Lycopene, the major tomato carotenoid, has been found to inhibit proliferation of several types of cancer cells, including those of breast, lung, and endometrium. By extending the work to the HL-60 promyelocytic leukemia cell line, we aimed to evaluate some mechanistic aspects of this effect. Particularly, the possibility was examined that the antiproliferative action of the carotenoid is associated with induction of cell differentiation. Lycopene treatment resulted in a concentration-dependent reduction in HL-60 cell growth as measured by [3H]thymidine incorporation and cell counting. This effect was accompanied by inhibition of cell cycle progression in the G0/G1 phase as measured by flow cytometry. Lycopene alone induced cell differentiation as measured by phorbol ester-dependent reduction of nitro blue tetrazolium and expression of the cell surface antigen CD14. Results of several recent intervention studies with beta-carotene, which have revealed no beneficial effects of this carotenoid, suggest that a single dietary component cannot explain the anticancer effect of diets rich in vegetables and fruits. Thus another goal of our study was to examine whether lycopene has the ability to synergize with other natural anticancer compounds, such as 1,25-dihydroxyvitamin D3, which when used alone are therapeutically active only at high and toxic concentrations. The combination of low concentrations of lycopene with 1,25-dihydroxyvitamin D3 exhibited a synergistic effect on cell proliferation and differentiation and an additive effect on cell cycle progression. Such synergistic antiproliferative and differentiating effects of lycopene and other compounds found in the diet and in plasma may suggest the inclusion of the carotenoid in the diet as a cancer-preventive measure.

Lycopene inhibition of cell cycle progression in breast and endometrial cancer cells is associated with reduction in cyclin D levels and retention of p27Kip1 in the cyclin E–cdk2 complexes

“…Giovannucci reviewed data from clinical and epidemiological studies and found that most of these studies show an inverse association between tomato intake or blood lycopene level and the risk of cancer . These epidemiological data are reinforced by studies showing the inhibitory e ect of lycopene on tumor cell growth in vitro (Amir et al, 1999;Countryman et al, 1991; and in vivo (Kim et al, 1997;Kobayashi et al, 1996;Nagasawa et al, 1995;Narisawa et al, 1996;Sharoni et al, 1997;.…”

“…We have recently shown that the inhibitory e ect of lycopene on leukemic (Amir et al, 1999) and breast (Karas et al, 2000) cancer cells is associated with the inhibition of cell cycle progression through G 1 phase. In this study we reveal the molecular changes underlying this action in breast and endometrial cancer cells.…”

“…Lycopene was dissolved in THF at a concentration of 2 mM and stored at 7208C. Immediately before the experiment, the stock solution was added to the cell culture medium, as described previously (Amir et al, 1999). The ®nal concentration of lycopene in the medium was measured by spectrophotometer after extraction in 2-propanol and n-hexane:dichloromethane (Levy et al, 1995).…”

“…We have previously demonstrated that lycopene inhibits the growth of mammary, endometrial, lung cancer (Levy et al, 1995) and leukemic (Amir et al, 1999) cells. This inhibition was associated with a delay in cell cycle progression from G 1 to S phase.…”

New Developments in Lycopene Analysis by Spectroscopic and Chromatographic Techniques, Accompanied With Mathematical Modelling

“…This induction of differentiation has been observed in leukemic cell cultures exposed to a combination of both lycopene and 1,25 dihydroxyvitamin D3 [85].…”