An
alpha-tocopherol,
beta-carotene supplementation trial (ATBC) and a
chemoprevention trial with
beta-carotene and
retinoids (CARET trial) were conducted in the 1990s in populations at risk for the development of
lung cancer. Both trials had to be discontinued due to significant increases in
lung cancer and cardiovascular mortality. Clinical trials to test the
cancer preventive effects of
beta-carotene are still ongoing, and high concentrations of this
provitamin are contained in numerous dietary supplements. Using a cell line derived from a human pulmonary
adenocarcinoma (PAC) of Clara cell lineage and immortalized human small airway epithelial cells, our data show that low concentrations of
beta-carotene that can be realistically expected in human tissues after
oral administration caused a significant increase in intracellular cAMP and activated PKA, as well as in phosphorylation of ERK1/2 and CREB. Furthermore, the proliferation of cells was significantly stimulated by identical concentrations of
beta-carotene as monitored by MTT assays. Control experiments with
retinol also showed stimulation of cell proliferation and activation of PKA in both cell lines. In light of the fact that PAC is the leading type of
lung cancer, these findings suggest that the growth promoting effects of
beta-carotene on this
cancer type observed in our experiments may have contributed to the unfortunate outcome of the ATBC and CARET trials. This interpretation is supported by the fact that elevated levels of cAMP in the cardiovascular system play a major role in the genesis of
cardiovascular disease, which was also greatly promoted in the CARET trial. Our data challenge the widely accepted view that
beta-carotene may be useful as a
cancer preventive agent.