Regulation of cell cycle progression and apoptosis by β‐carotene in undifferentiated and differentiated HL‐60 leukemia cells: Possible involvement of a redox mechanism

Although epidemiologic studies have demonstrated that a high intake of vegetables containing β‐carotene lowers the risk of cancer, recent intervention studies have revealed that β‐carotene supplementation to smokers resulted in a high incidence of lung cancer. We hypothesized that β‐carotene may act as a pro‐ or anticancerogenic agent by modulating pathways involved in cell growth and that such a modulation may involve a redox mechanism. To test this hypothesis, cell proliferation, apoptosis and redox status were evaluated in undifferentiated and dimethylsulfoxide‐differentiated HL‐60 cells exposed to β‐carotene. The carotenoid modified cell cycle progression and induced apoptosis in a dose‐dependent manner. These effects were more remarkable in undifferentiated cells than in differentiated cells. In accord with these findings, in undifferentiated cells, β‐carotene was more effective in decreasing cyclin A and Bcl‐2 expression and in increasing p21 and p27 expression. Neither Bcl‐xL nor Bax expression were significantly modified by the carotenoid. From a mechanistic point of view, the delay in cell growth by β‐carotene was highly coincident with the increased intracellular reactive oxygen species production and oxidized glutathione content induced by the carotenoid. Moreover, α‐tocopherol minimized the effects of β‐carotene on cell growth. These data provide evidence that β‐carotene modulates molecular pathways involved in cell cycle progression and apoptosis and support the hypothesis that a redox mechanism may be implicated. They also suggest that differentiated cells may be less susceptible to the carotenoid than highly neoplastic undifferentiated cells. © 2001 Wiley‐Liss, Inc.