Induction of cell cycle arrest and apoptosis in human colon adenocarcinoma cell lines by β-carotene through down-regulation of cyclin A and Bcl-2 family proteins

Although the pharmacological role of β-carotene in the prevention and treatment of colon cancer has received increasing attention, little is known about the molecular mechanisms of action of this carotenoid. The present study demonstrates that β-carotene, a natural pigment widely present in fruit and vegetables, inhibits the growth of several human colon adenocarcinoma cell lines (COLO 320 HSR, LS-174, HT-29 and WiDr) by inducing cell cycle arrest in G2/M phase and apoptosis. These effects were dose and time dependent and strictly related to cell ability to accumulate the carotenoid. COLO 320 HSR cells incorporated β-carotene to a greater extent than LS-174, HT-29 and WiDr cells and, concomitantly, they exhibited a higher sensitivity to the growth inhibitory effects of the carotenoid. At inhibitory concentrations β-carotene reduced the expression of cyclin A, a key regulator of G2/M progression. Neither p21 nor p27, two cyclin kinase inhibitors, were significantly modified by carotenoid treatment. With respect to apoptosis induction, decreased levels of the apoptosis blocking proteins Bcl-2 and Bcl-xL were also observed. On the other hand, no changes in expression of the apoptosis promoter protein Bax were detected. This study represents a novel aspect of the biological profile of β-carotene and a new step in elucidating the underlying molecular mechanisms of its antitumor action. In addition, since cell growth inhibitory effects were reached at β-carotene concentrations achievable in vivo following its supplementation, this study provides a rational approach for the use of β-carotene in colon cancer.